Note: Descriptions are shown in the official language in which they were submitted.
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GCN2 INHIBITORS AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. 119(e) of U.S.
Provisional
Application no. 62/623,312, filed January 29, 2018, the content of which is
incorporated herein in
its entirety by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to compounds and methods useful for
inhibiting General
amino acid Control Non-derepressible 2 kinase ("GCN2"). The invention also
provides
pharmaceutically acceptable compositions comprising compounds of the present
invention and
methods of using said compositions in the treatment of various disorders.
BACKGROUND OF THE INVENTION
[0003] GCN2 (General amino acid Control Non-derepressible 2) is a
ubiquitously expressed
protein kinase involved in cellular responses to amino acid deficiency across
eukaryotes (Castilho
et al., 2014). Cellular deficiency in one or more amino acids causes the
accumulation of uncharged
cognate transfer RNAs (tRNAs), which are bound directly by GCN2, leading to
kinase activation
and phosphorylation of eukaryotic initiation factor 2 a (eIF2a) on Serine 51
(Wek et al., 1989;
Dong et al., 2000). Phosphorylation of eIF2a results in initiation of protein
translation, which
causes a reduction in the translation of most mRNAs leading to reduced global
utilization of amino
acids. Simultaneously, eIF2a phosphorylation increases the translation of a
specific subset of
mRNAs containing certain upstream open reading frames in their 5' untranslated
regions (5'-
UTRs), such as the transcription factor ATF4 in mammals (Vattem and Wek,
2004), which
promotes restoration of protein homeostasis. GCN2 is therefore a critical
determinant of cell fate
in response to amino acid depletion.
[0004] Induction of cellular responses to amino acid deficiency is emerging
as an important
mechanism for regulation of the mammalian immune system, particularly in
certain disease
settings including cancer and autoimmunity. Various immunosuppressive cell
types implicated in
the control of immune responses in these settings, including tolerogenic
dendritic cells, myeloid
derived suppressor cells (MDSCs), tolerogenic/M2 macrophages and cancer cells
themselves,
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have each been reported to use the depletion of amino acids to suppress T-cell
responses (Munn et
al., 2004; Munn et al., 2005; Rodriguez et al., 2010; Whyte et al., 2011;
Uyttenhove et al., 2003).
This is achieved by the intracellular transport of amino acids coupled with
the overexpression of
amino acid catabolizing enzymes in these cells, such as the tryptophan
catabolizing enzymes
indoleamine 2,3 dioxygenase (DO) and tryptophan 2,3 dioxygenase (TDO), and the
arginine
catabolizing enzymes arginase 1 and 2 (ARG1, ARG2). As a result, these cells
can reduce the local
extracellular concentrations of specific amino acids wherever they reside, and
therefore induce
GCN2 activity in nearby T-cells in an antigen-specific manner (Munn et al.,
2004). In the mouse
system both in vitro and in vivo, the depletion of local tryptophan or
arginine concentrations, for
example by DO- or ARG1-expressing dendritic cells, has been reported to induce
proliferative
arrest and anergy in T-cells in a GCN2-dependent manner (Munn et al., 2005;
Rodriguez et al.,
2007; Fletcher et al., 2015). In addition, the induction and/or maintenance of
MDSCs and
immunosuppressive regulatory T-cells (T-regs) may also be dependent on GCN2
activity under
amino acid depleted conditions (Fletcher et al., 2015; Fallarino et al.,
2006). Finally, other work
implicates the activation of GCN2 by DO within tolerogenic macrophages as a
key mechanism
for suppressing systemic autoimmune responses to apoptotic cells (Ravishankar
et al., 2015).
These findings identify GCN2 as a potentially key effector of the
immunosuppressive effects of
amino acid depletion associated with various disease states.
[0005] Incipient cancers need to evade host anti-cancer immunity in order
to thrive (Corthay,
2014). This can be achieved by modulating tumor antigen presentation and/or by
using tumor
immune evasion mechanisms to actively suppress immune attack. High expression
of amino acid
catabolising enzymes such as DO and ARG1 has been observed across a large
proportion of
cancer patients with various tumor types, both in the cancer cells themselves
and in
immunosuppressive host cell types that accumulate in tumors, tumor-draining
lymph nodes and/or
the peripheral circulation (Uyttenhove et al., 2003; Pilotte et al., 2012; Zea
et al., 2005). Amino
acid depletion may therefore be a powerful and widespread immune evasion
mechanism whereby
anti-cancer immunity is restrained. Consistently, amino acid depletion in both
tumors and tumor-
draining lymph nodes has been established as a resistance mechanism to
existing immuno-
oncology agents, including checkpoint receptor blocking antibodies, in several
syngeneic mouse
tumor models (Holmgaard et al., 2013; Spranger et al., 2014). On this basis,
inhibitors of DO and
TDO are now being progressed in clinical trials for cancer and inhibitors of
additional amino acid
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catabolases are in preclinical development. Accordingly, inhibitors of GCN2
may also be useful
for cancer treatment by disrupting the nodal effector signal of amino acid
depletion in the immune
system and enabling an anti-cancer immune response. Genetic ablation of GCN2
is well tolerated
in mice under standard growth conditions (Zhang et al., 2002), and inhibitors
of GCN2 may have
broader utility than inhibitors of individual amino acid catabolases because
GCN2 responds to
depletion of several different amino acids.
[0006] In addition, GCN2 activation and overexpression has been observed in
various human
tumors compared with normal tissues (Ye et al., 2010; Wang et al., 2013).
Depletion of GCN2
reduced the growth of mouse embryonic fibroblasts and human cancer cells in
vitro under severe
amino acid or glucose depleted conditions, and blocked the growth of human
tumor xenografts in
mice (Ye et al., 2010). GCN2 inhibitors may therefore have direct anti-cancer
effects due to the
frequent disruption of nutrient supply in the tumor microenvironment.
[0007] For these reasons, there is a need for the development of potent and
selective inhibitors
of GCN2 for the treatment of cancer, either as single agents or in
combination, for example with
anti-CTLA4 and anti-PD1/PD-L1 checkpoint blocking antibodies.
SUMMARY OF THE INVENTION
[0008] It has now been found that compounds of this invention, and
pharmaceutically
acceptable compositions thereof, are effective as inhibitors of GCN2 kinase.
Such compounds
have the general formula I:
(R4)P
(R3)(1
NN A (R1),
-(R2)n
or a pharmaceutically acceptable salt thereof, wherein each variable is as
defined and described
herein.
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[0009] Compounds of the present invention, and pharmaceutically acceptable
compositions
thereof, are useful for treating a variety of diseases, disorders or
conditions, associated with
regulation of signaling pathways implicating GCN2 kinase. Such diseases,
disorders, or conditions
include those described herein.
[0010] Compounds provided by this invention are also useful for the study
of the GCN2
enzyme in biological and pathological phenomena; the study of intracellular
signal transduction
pathways occurring in bodily tissues; and the comparative evaluation of new
GCN2 inhibitors or
other regulators of kinases, signaling pathways, and cytokine levels in vitro
or in vivo.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
1. General Description of Certain Embodiments of the Invention:
[0011] Compounds of the present invention, and compositions thereof, are
useful as inhibitors
of GCN2 protein kinase. In some embodiments, a provided compound inhibits
GCN2.
[0012] In certain embodiments, the present invention provides a compound of
formula I:
(R4)P
(R3)(1
N1N A (R1)ni
-(R2)n
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from a 3-8 membered saturated or partially unsaturated
monocyclic carbocyclic
ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8
membered partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, or sulfur optionally fused to a 5-6 membered aromatic ring
having 0-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12
membered partially
unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bicyclic
heterocyclic ring
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having 1-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 7-12 membered
partially unsaturated bridged bicyclic heterocyclic ring having 1-2
heteroatoms independently
selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic
heteroaromatic ring having
1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-
10 membered
bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected
from nitrogen,
oxygen, or sulfur, or
Het, wherein Het is a 4-8 membered saturated monocyclic heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12
membered saturated
spirocyclic heterocyclic ring having 1-4 heteroatoms independently selected
from nitrogen,
oxygen, or sulfur, a 7-12 membered saturated bicyclic heterocyclic ring having
1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered
saturated bridged
bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from
nitrogen, oxygen,
or sulfur;
(R4)p (R4)p (R4)P
--X,... (R4)p
- N
N/,
1 lz, _1_ 1
\N/\N/) Y
.,.., Nsiss V \ / ,
Ring B is ,
(R4)p (R4)10 p
FeP
N N/i(R4) (R4) ()
P
i I I )Ni-E'Cl -CI) jeYi
`?zz2sig \zz77\sssss \ /
, \ , ,
(R4)p
N(R4)p (R4)p
N' N S¨N N¨S
,. ,.....)!,
\,Nsi l'Iltstss ''%, ,r," \ N / \ N
0 0
(R4)p (R4)p (R4)
HN7.,...L......(R4)13 - = - - \ z ,_, LL
N N1 'l V ssss
, or .
, ,
each R is independently hydrogen or an optionally substituted group selected
from C1.6 aliphatic,
a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring,
phenyl, an 8-10
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membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or
partially unsaturated
monocyclic heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen,
oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4
heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered
bicyclic
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen, oxygen, or
sulfur; or
two R groups are optionally taken together to form a bivalent C2-4 alkylene
chain;
two R groups are optionally taken together with their intervening atoms to
form an optionally
substituted 3-7-membered saturated or partially unsaturated monocyclic ring
having 0-4
heteroatoms independently selected from nitrogen, oxygen or sulfur;
each R' is independently hydrogen or a C1-3 aliphatic group optionally
substituted with halogen;
each of RI- is independently hydrogen, halogen, -CN, -NO2, -C(0)R, -C(0)0R, -
C(0)NR2, -
C (0)NR S (0)2R, -C (0)N= S (0)R2, -NR2, -NRC (0)R, -NRC (0)NR2, -NRC (0)0R, -
NRS (0)2R,
-NRS(0)2NR2, -OR, -0N(R)S02R, -P(0)R2, -SR, -S(0)R, -S(0)2R, -S(0)(NH)R, -
S(0)2N(R)2, -S(NH2)2(0)0H, -N=S(0)R2, -CH3, -CH2OH, -CH2NHSO2CH3, -CH3, -
CH2OH, -
CH2NHS 02CH3, -CD3, -CD2NRS (0)2R, or R; or:
two Rl groups are optionally taken together to form =0 or =NH; or
two Rl groups are optionally taken together to form a bivalent C2-4 alkylene
chain;
each of R2 is independently hydrogen, halogen, -CN, -C(0)N(R')2, -OR', -
N(R')2, -S(0)2R, -
S(0)2N(R)2, -0-phenyl, or an optionally substituted group selected from C1-3
aliphatic, phenyl, 5-
6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, or sulfur, or 4-8 membered saturated monocyclic heterocycle
having 1-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R3 is hydrogen, halogen, -CN, -OR', -N(R')2, or an optionally substituted
group selected from
C1-3 aliphatic, phenyl, or a 5-6 membered monocyclic heteroaromatic ring
having 1-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur;
R4 is hydrogen, halogen, -CN, -OR, -N=S(0)R2, -N(R)2, or an optionally
substituted group
selected from C1-3 aliphatic, a 4-8 membered saturated or partially
unsaturated monocyclic
heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen,
oxygen, or sulfur,
or a 7-12 membered saturated or partially unsaturated spirocyclic heterocyclic
ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, or sulfur;
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m is 0, 1, 2, 3, 4 or 5;
n is 0, 1, or 2;
p is 0 or 1; and
q is 0 or 1.
2. Compounds and Definitions:
[0013] Compounds of the present invention include those described generally
herein, and are
further illustrated by the classes, subclasses, and species disclosed herein.
As used herein, the
following definitions shall apply unless otherwise indicated. For purposes of
this invention, the
chemical elements are identified in accordance with the Periodic Table of the
Elements, CAS
version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general
principles of organic
chemistry are described in "Organic Chemistry", Thomas Sorrell, University
Science Books,
Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.:
Smith, M.B. and
March, J., John Wiley & Sons, New York: 2001, the entire contents of which are
hereby
incorporated by reference.
[0014] The term "aliphatic" or "aliphatic group", as used herein, means a
straight-chain (i.e.,
unbranched) or branched, substituted or unsubstituted hydrocarbon chain that
is completely
saturated or that contains one or more units of unsaturation, or a monocyclic
hydrocarbon or
bicyclic hydrocarbon that is completely saturated or that contains one or more
units of
unsaturation, but which is not aromatic (also referred to herein as
"carbocycle," "cycloaliphatic"
or "cycloalkyl"), that has a single point of attachment to the rest of the
molecule. Unless otherwise
specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some
embodiments, aliphatic
groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic
groups contain 1-4
aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-
3 aliphatic carbon
atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic
carbon atoms. In some
embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a
monocyclic C3-C6
hydrocarbon that is completely saturated or that contains one or more units of
unsaturation, but
which is not aromatic, that has a single point of attachment to the rest of
the molecule. Suitable
aliphatic groups include, but are not limited to, linear or branched,
substituted or unsubstituted
alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,
(cycloalkenyl)alkyl
or (cycloalkyl)alkenyl.
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[0015] As used herein, the term "bridged bicyclic" refers to any bicyclic
ring system, i.e.
carbocyclic or heterocyclic, saturated or partially unsaturated, having at
least one bridge. As
defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or a
valence bond
connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the
ring system which
is bonded to three or more skeletal atoms (excluding hydrogen). In some
embodiments, a bridged
bicyclic group has 7-12 ring members and 0-4 heteroatoms independently
selected from nitrogen,
oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and
include those groups
set forth below where each group is attached to the rest of the molecule at
any substitutable carbon
or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is
optionally substituted
with one or more substituents as set forth for aliphatic groups. Additionally
or alternatively, any
substitutable nitrogen of a bridged bicyclic group is optionally substituted.
Exemplary bridged
bicyclics include:
\ \NH
HN
o
0
rN H1
0 -po HNO
NH NH CNH
S1H
0
[0016] The term "lower alkyl" refers to a C1-4 straight or branched alkyl
group. Exemplary
lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and
tert-butyl.
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[0017] The term "lower haloalkyl" refers to a C1-4 straight or branched
alkyl group that is
substituted with one or more halogen atoms.
[0018] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen,
phosphorus, or
silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or
silicon; the quaternized
form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic
ring, for example N (as in
3,4-dihydro-2H-pyrroly1), NH (as in pyrrolidinyl) or NIt+ (as in N-substituted
pyrrolidinyl)).
[0019] The term "unsaturated," as used herein, means that a moiety has one
or more units of
unsaturation.
[0020] As used herein, the term "bivalent C1-8 (or C1.6) saturated or
unsaturated, straight or
branched, hydrocarbon chain", refers to bivalent alkylene, alkenylene, and
alkynylene chains that
are straight or branched as defined herein.
[0021] The term "alkylene" refers to a bivalent alkyl group. An "alkylene
chain" is a
polymethylene group, i.e., ¨(CH2),¨, wherein n is a positive integer,
preferably from 1 to 6, from
1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain
is a polymethylene
group in which one or more methylene hydrogen atoms are replaced with a
substituent. Suitable
substituents include those described below for a substituted aliphatic group.
[0022] The term "alkenylene" refers to a bivalent alkenyl group. A
substituted alkenylene
chain is a polymethylene group containing at least one double bond in which
one or more hydrogen
atoms are replaced with a substituent. Suitable substituents include those
described below for a
substituted aliphatic group.
[0023] As used herein, the term "cyclopropylenyl" refers to a bivalent
cyclopropyl group of
risc*'It
the following structure:
[0024] The term "halogen" means F, Cl, Br, or I.
[0025] The term "aryl" used alone or as part of a larger moiety as in
"aralkyl," "aralkoxy," or
"aryloxyalkyl," refers to monocyclic or bicyclic ring systems having a total
of five to fourteen ring
members, wherein at least one ring in the system is aromatic and wherein each
ring in the system
contains 3 to 7 ring members. The term "aryl" may be used interchangeably with
the term "aryl
ring." In certain embodiments of the present invention, "aryl" refers to an
aromatic ring system
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which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and
the like, which may
bear one or more substituents. Also included within the scope of the term
"aryl," as it is used
herein, is a group in which an aromatic ring is fused to one or more
non¨aromatic rings, such as
indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl,
and the like.
[0026] The terms "heteroaryl" and "heteroar¨," used alone or as part of a
larger moiety, e.g.,
"heteroaralkyl," or "heteroaralkoxy," refer to groups having 5 to 10 ring
atoms, preferably 5, 6, or
9 ring atoms; having 6, 10, or 14 7C electrons shared in a cyclic array; and
having, in addition to
carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to
nitrogen, oxygen, or
sulfur, and includes any oxidized form of nitrogen or sulfur, and any
quaternized form of a basic
nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl,
pyrrolyl, imidazolyl,
pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiazolyl, isothiazolyl,
thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,
purinyl, naphthyridinyl, and
pteridinyl. The terms "heteroaryl" and "heteroar¨", as used herein, also
include groups in which a
heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or
heterocyclyl rings, where the
radical or point of attachment is on the heteroaromatic ring. Nonlimiting
examples include indolyl,
i soindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl,
benzimidazolyl, b enzthi az olyl,
quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
4H¨quinolizinyl,
carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
tetrahydroquinolinyl,
tetrahydroisoquinolinyl, and pyrido[2,3¨b]-1,4¨oxazin-3(4H)¨one. A heteroaryl
group may be
mono¨ or bicyclic. The term "heteroaryl" may be used interchangeably with the
terms "heteroaryl
ring," "heteroaryl group," or "heteroaromatic," any of which terms include
rings that are optionally
substituted. The term "heteroaralkyl" refers to an alkyl group substituted by
a heteroaryl, wherein
the alkyl and heteroaryl portions independently are optionally substituted.
[0027] As used herein, the terms "heterocycle," "heterocyclyl,"
"heterocyclic radical," and
"heterocyclic ring" are used interchangeably and refer to a stable 5¨ to
7¨membered monocyclic
or 7-10¨membered bicyclic heterocyclic moiety that is either saturated or
partially unsaturated,
and having, in addition to carbon atoms, one or more, preferably one to four,
heteroatoms, as
defined above. When used in reference to a ring atom of a heterocycle, the
term "nitrogen" includes
a substituted nitrogen. As an example, in a saturated or partially unsaturated
ring having 0-3
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heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N
(as in 3,4¨dihydro-
2H¨pyrroly1), NH (as in pyrrolidinyl), or +1\TR (as in N¨substituted
pyrrolidinyl).
[0028] A heterocyclic ring can be attached to its pendant group at any
heteroatom or carbon
atom that results in a stable structure and any of the ring atoms can be
optionally substituted.
Examples of such saturated or partially unsaturated heterocyclic radicals
include, without
limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl,
pyrrolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,
oxazolidinyl, piperazinyl,
dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and
quinuclidinyl. The
terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic
group," "heterocyclic
moiety," and "heterocyclic radical," are used interchangeably herein, and also
include groups in
which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or
cycloaliphatic rings, such as
indolinyl, 3H¨indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A
heterocyclyl group
may be mono¨ or bicyclic. The term "heterocyclylalkyl" refers to an alkyl
group substituted by a
heterocyclyl, wherein the alkyl and heterocyclyl portions independently are
optionally substituted.
[0029] As used herein, the term "partially unsaturated" refers to a ring
moiety that includes at
least one double or triple bond. The term "partially unsaturated" is intended
to encompass rings
having multiple sites of unsaturation, but is not intended to include aryl or
heteroaryl moieties, as
herein defined.
[0030] As described herein, compounds of the invention may contain
"optionally substituted"
moieties. In general, the term "substituted," whether preceded by the term
"optionally" or not,
means that one or more hydrogens of the designated moiety are replaced with a
suitable substituent.
Unless otherwise indicated, an "optionally substituted" group may have a
suitable substituent at
each substitutable position of the group, and when more than one position in
any given structure
may be substituted with more than one substituent selected from a specified
group, the substituent
may be either the same or different at every position. Combinations of
substituents envisioned by
this invention are preferably those that result in the formation of stable or
chemically feasible
compounds. The term "stable," as used herein, refers to compounds that are not
substantially
altered when subjected to conditions to allow for their production, detection,
and, in certain
embodiments, their recovery, purification, and use for one or more of the
purposes disclosed
herein.
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[0031]
Suitable monovalent substituents on a substitutable carbon atom of an
"optionally
substituted" group are independently halogen; ¨(CH2)0_4R ; ¨(CH2)0_40R ; -
0(CH2)0_4R , ¨0¨
(CH2)0_4C(0)0R ; ¨(CH2)0_4CH(OR )2; ¨(CH2)0_4SR ; ¨(CH2)0_4Ph, which may be
substituted
with R ; ¨(CH2)0_40(CH2)0_11311 which may be substituted with R ; ¨CH=CHPh,
which may be
substituted with R ; ¨(CH2)0_40(CH2)0_1-pyridyl which may be substituted with
R ; ¨NO2; ¨CN;
¨N3; -(CH2)0_4N(W))2; ¨(CH2)0_4N(R )C(0)R ; ¨N(R )C(S)R ;
¨(CH2)0-
4N(R )C(0)NR 2; -N(R )C(S)NR 2; ¨(CH2)0_4N(R )C(0)0R ;
N(R )N(R )C(0)R ; -N(R )N(R )C(0)NR 2; -N(R )N(R )C(0)0R ; ¨(CH2)0_4C(0)R ; ¨
C(S)R ; ¨(CH2)0_4C(0)0R ; ¨(CH2)0_4C(0)SR ; -(CH2)0_4C(0)0 SiR 3;
¨(CH2)0_40C(0)R ; ¨
OC(0)(CH2)0_45R¨, ¨SC(S)SR ; ¨(CH2)0_4 SC(0)R ; ¨(CH2)0_4C(0)NR 2; ¨C(S)NR 2;
¨
C(S)SR ; -(CH2)0_40C(0)NR 2; -C(0)N(OR )R ; ¨C(0)C(0)R ; ¨C(0)CH2C(0)R ; ¨
C(NOR )R ; -(CH2)0_4 S SR ; ¨(CH2)0_4 S (0)2R ; ¨(CH2)0_4 S (0)20R ;
¨(CH2)0_40 S(0)2R ; ¨
S(0)2NR 2; -(CE12)0_4 S (0)R ; -(CH2)0_4 S(0)(NR )R ;
-N(R )S(0)2NR 2;
N(R )S(0)2R ; -N(R )S(0)(NR )R 2; ¨N(OR )R ; -N=S(0)R 2; ¨N(OR )502R ;
¨C(NH)NR 2;
¨P(0)2R ; -P(0)R 2; -0P(0)R 2; ¨0P(0)(OR )2; ¨SiR 3; ¨(Ci_4 straight or
branched alkylene)0¨
N(R )2; or ¨(Ci_4 straight or branched alkylene)C(0)0¨N(R )2, wherein each R
may be
substituted as defined below and is independently hydrogen, C1_6 aliphatic,
¨CH2Ph, ¨0(CH2)o-
-CH2-(5-6 membered heteroaryl ring), or a 5-6¨membered saturated, partially
unsaturated, or
aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen,
or sulfur, or,
notwithstanding the definition above, two independent occurrences of R , taken
together with their
intervening atom(s), form a 3-12¨membered saturated, partially unsaturated, or
aryl mono¨ or
bicyclic ring having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur,
which may be substituted as defined below.
[0032]
Suitable monovalent substituents on R (or the ring formed by taking two
independent
occurrences of R together with their intervening atoms), are independently
halogen, ¨(CH2)0_21e,
¨(halole), ¨(CH2)0_20H, ¨(CH2)0_201e, ¨(CH2)0_2CH(0R.)2; -0(halole), ¨CN, ¨N3,
¨(CH2)0-
2C(0)1e, ¨(CH2)0_2C(0)0H, ¨(CH2)0_2C(0)01e, ¨(CH2)0_25R., ¨(CH2)0_25H, ¨(CH2)0-
2NH2, ¨
(CH2)0_2NHie, ¨(CH2)0_2NR.2, ¨NO2, -
C(0)5le, ¨(Ci_4 straight or branched
alkylene)C(0)01e, or ¨SSR. wherein each le is unsubstituted or where preceded
by "halo" is
substituted only with one or more halogens, and is independently selected from
C1-4 aliphatic, -
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CH2Ph, ¨0(CH2)0_11311, or a 5-6¨membered saturated, partially unsaturated, or
aryl ring having 0-
4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable divalent
substituents on a saturated carbon atom of R include =0 and =S.
[0033] Suitable divalent substituents on a saturated carbon atom of an
"optionally substituted"
group include the following: =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*,
=NNHS(0)2R*,
=NR*, =NOR*, ¨0(C(R*2))2_30¨, or ¨S(C(R*2))2_35¨, wherein each independent
occurrence of R*
is selected from hydrogen, C1_6 aliphatic which may be substituted as defined
below, or an
unsubstituted 5-6¨membered saturated, partially unsaturated, or aryl ring
having 0-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. Suitable divalent
substituents that are
bound to vicinal substitutable carbons of an "optionally substituted" group
include: ¨0(CR*2)2_
30¨, wherein each independent occurrence of R* is selected from hydrogen, C1-6
aliphatic which
may be substituted as defined below, or an unsubstituted 5-6¨membered
saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen,
or sulfur.
[0034] Suitable substituents on the aliphatic group of R* include halogen,
¨R., -(halole), -OH,
¨01e, ¨0(halole), ¨CN, ¨C(0)0H, ¨C(0)01e, ¨NH2, ¨NHie, ¨NR.2, or ¨NO2, wherein
each
R is unsubstituted or where preceded by "halo" is substituted only with one or
more halogens,
and is independently C1_4 aliphatic, ¨CH2Ph, ¨0(CH2)0_11311, or a 5-6¨membered
saturated,
partially unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen,
oxygen, or sulfur.
[0035] Suitable substituents on a substitutable nitrogen of an "optionally
substituted" group
include ¨C(0)1e, ¨C(0)01e, ¨C(0)C(0)1e,
C(0)CH2C(0)1e, -S(0)21e, -S(0)2NR1.2, ¨C(S)NR1.2, ¨C(NH)NR1.2, or
¨N(R1)S(0)21e; wherein
each Itt is independently hydrogen, C1-6 aliphatic which may be substituted as
defined below,
unsubstituted ¨0Ph, or an unsubstituted 5-6¨membered saturated, partially
unsaturated, or aryl
ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or,
notwithstanding the definition above, two independent occurrences of le, taken
together with their
intervening atom(s) form an unsubstituted 3-12¨membered saturated, partially
unsaturated, or aryl
mono¨ or bicyclic ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or
sulfur.
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[0036] Suitable substituents on the aliphatic group of Itt are
independently halogen, ¨
1e, -(haloR*), ¨OH, ¨01e, ¨0(halole), ¨CN, ¨C(0)0H, ¨C(0)01e, ¨NH2, ¨NUR',
¨NR.2,
or -NO2, wherein each le is unsubstituted or where preceded by "halo" is
substituted only with
one or more halogens, and is independently C1_4 aliphatic, ¨CH2Ph,
¨0(CH2)0_11311, or a 5-6¨
membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms
independently
selected from nitrogen, oxygen, or sulfur.
[0037] As used herein, the term "pharmaceutically acceptable salt" refers
to those salts which
are, within the scope of sound medical judgment, suitable for use in contact
with the tissues of
humans and lower animals without undue toxicity, irritation, allergic response
and the like, and
are commensurate with a reasonable benefit/risk ratio. Pharmaceutically
acceptable salts are well
known in the art. For example, S. M. Berge et al., describe pharmaceutically
acceptable salts in
detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by
reference.
Pharmaceutically acceptable salts of the compounds of this invention include
those derived from
suitable inorganic and organic acids and bases. Examples of pharmaceutically
acceptable,
nontoxic acid addition salts are salts of an amino group formed with inorganic
acids such as
hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with
organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid,
citric acid, succinic acid
or malonic acid or by using other methods used in the art such as ion
exchange. Other
pharmaceutically acceptable salts include adipate, alginate, ascorbate,
aspartate, benzenesulfonate,
benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate,
fumarate,
glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,
hexanoate, hydroiodide, 2¨
hydroxy¨ethane sulfonate, lactobionate, lactate, laurate, lauryl sulfate, m al
ate, m al eate, m al onate,
methanesulfonate, 2¨naphthalenesulfonate, nicotinate, nitrate, oleate,
oxalate, palmitate, pamoate,
pectinate, persulfate, 3¨phenylpropionate, phosphate, pivalate, propionate,
stearate, succinate,
sulfate, tartrate, thiocyanate, p¨toluenesulfonate, undecanoate, valerate
salts, and the like.
[0038] Salts derived from appropriate bases include alkali metal, alkaline
earth metal,
ammonium and N+(C1_4alky1)4 salts. Representative alkali or alkaline earth
metal salts include
sodium, lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically
acceptable salts include, when appropriate, nontoxic ammonium, quaternary
ammonium, and
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amine cations formed using counterions such as halide, hydroxide, carboxylate,
sulfate, phosphate,
nitrate, loweralkyl sulfonate and aryl sulfonate.
[0039] Unless otherwise stated, structures depicted herein are also meant
to include all
isomeric (e.g., enantiomeric, diastereomeric, and geometric (or
conformational)) forms of the
structure; for example, the R and S configurations for each asymmetric center,
Z and E double
bond isomers, and Z and E conformational isomers. Therefore, single
stereochemical isomers as
well as enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present
compounds are within the scope of the invention. Unless otherwise stated, all
tautomeric forms of
the compounds of the invention are within the scope of the invention.
Additionally, unless
otherwise stated, structures depicted herein are also meant to include
compounds that differ only
in the presence of one or more isotopically enriched atoms. For example,
compounds having the
present structures including the replacement of hydrogen by deuterium or
tritium, or the
replacement of a carbon by a '3C- or '4C-enriched carbon are within the scope
of this invention.
Such compounds are useful, for example, as analytical tools, as probes in
biological assays, or as
therapeutic agents in accordance with the present invention. In certain
embodiments, Rx, of a
provided compound comprises one or more deuterium atoms.
[0040] As used herein, the term "inhibitor" is defined as a compound that
binds to and /or
inhibits GCN2 with measurable affinity. In certain embodiments, an inhibitor
has an IC50 and/or
binding constant of less than about 50 uM, less than about 1 uM, less than
about 500 nM, less than
about 100 nM, less than about 10 nM, or less than about 1 nM.
[0041] A compound of the present invention may be tethered to a detectable
moiety. It will
be appreciated that such compounds are useful as imaging agents. One of
ordinary skill in the art
will recognize that a detectable moiety may be attached to a provided compound
via a suitable
substituent. As used herein, the term "suitable substituent" refers to a
moiety that is capable of
covalent attachment to a detectable moiety. Such moieties are well known to
one of ordinary skill
in the art and include groups containing, e.g., a carboxylate moiety, an amino
moiety, a thiol
moiety, or a hydroxyl moiety, to name but a few. It will be appreciated that
such moieties may be
directly attached to a provided compound or via a tethering group, such as a
bivalent saturated or
unsaturated hydrocarbon chain. In some embodiments, such moieties may be
attached via click
chemistry. In some embodiments, such moieties may be attached via a 1,3-
cycloaddition of an
CA 03089769 2020-07-27
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azide with an alkyne, optionally in the presence of a copper catalyst. Methods
of using click
chemistry are known in the art and include those described by Rostovtsev et
at., Angew. Chem.
Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-
57.
[0042] As used herein, the term "detectable moiety" is used interchangeably
with the term
"label" and relates to any moiety capable of being detected, e.g., primary
labels and secondary
labels. Primary labels, such as radioisotopes (e.g., tritium, 32P, 33P, 35, or
14C), mass-tags, and
fluorescent labels are signal generating reporter groups which can be detected
without further
modifications. Detectable moieties also include luminescent and phosphorescent
groups.
[0043] The term "secondary label" as used herein refers to moieties such as
biotin and various
protein antigens that require the presence of a second intermediate for
production of a detectable
signal. For biotin, the secondary intermediate may include streptavidin-enzyme
conjugates. For
antigen labels, secondary intermediates may include antibody-enzyme
conjugates. Some
fluorescent groups act as secondary labels because they transfer energy to
another group in the
process of nonradiative fluorescent resonance energy transfer (FRET), and the
second group
produces the detected signal.
[0044] The terms "fluorescent label", "fluorescent dye", and "fluorophore"
as used herein refer
to moieties that absorb light energy at a defined excitation wavelength and
emit light energy at a
different wavelength. Examples of fluorescent labels include, but are not
limited to: Alexa Fluor
dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546,
Alexa Fluor 568,
Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA,
AMCA-S,
BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550,
BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY
630/650,
BODIPY 650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,
Cascade
Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl,
Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-dimethoxy-fluorescein, DM-NERF,
Eosin,
Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD
800), JOE,
Lissamine rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein,
Oregon Green 488,
Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B,
Rhodamine
6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-
bromosulfone-
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fluorescein, Tetramethyl-rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA),
Texas
Red, Texas Red-X.
[0045]
The term "mass-tag" as used herein refers to any moiety that is capable of
being
uniquely detected by virtue of its mass using mass spectrometry (MS) detection
techniques.
Examples of mass-tags include electrophore release tags such as N-[3-[4' -[(p-
Methoxytetrafluorob enzyl)oxy] pheny1]-3 -methyl glyceronyl] i sonipecoti c
Acid, 4' 42,3,5,6-
Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their
derivatives. The synthesis
and utility of these mass-tags is described in United States Patents
4,650,750, 4,709,016,
5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other
examples of mass-
tags include, but are not limited to, nucleotides, dideoxynucleotides,
oligonucleotides of varying
length and base composition, oligopeptides, oligosaccharides, and other
synthetic polymers of
varying length and monomer composition. A large variety of organic molecules,
both neutral and
charged (biomolecules or synthetic compounds) of an appropriate mass range
(100-2000 Daltons)
may also be used as mass-tags.
[0046]
The terms "measurable affinity" and "measurably inhibit," as used herein,
means a
measurable change in a GCN2 protein kinase activity between a sample
comprising a compound
of the present invention, or composition thereof, and a GCN2 protein kinase,
and an equivalent
sample comprising a GCN2 protein kinase, in the absence of said compound, or
composition
thereof.
3. Description of Exemplary Embodiments:
[0047]
As described above, in certain embodiments, the present invention provides a
compound of formula I:
(R4)P
(R3)(1
N1 N A (R1 )m
-(R2)n
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or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from a 3-8 membered saturated or partially unsaturated
monocyclic carbocyclic
ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8
membered
partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms
independently
selected from nitrogen, oxygen, or sulfur optionally fused to a 5-6 membered
aromatic ring
having 0-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 7-12
membered partially unsaturated spirocyclic heterocyclic ring having 1-2
heteroatoms
independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered
partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bridged
bicyclic
heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen,
oxygen, or
sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered
bicyclic
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen, oxygen,
or sulfur, or
Het, wherein Het is a 4-8 membered saturated monocyclic heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12
membered
saturated spirocyclic heterocyclic ring having 1-4 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, a 7-12 membered saturated bicyclic
heterocyclic ring
having 1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a
7-12 membered saturated bridged bicyclic heterocyclic ring having 1-2
heteroatoms
independently selected from nitrogen, oxygen, or sulfur;
( R4) p (R4 )p ( R4)P
/(R4)P
- N //
N N N
11
Ring B is \rN
(R4)p (R4
) )
N/(R4p
\P
N N /1(R4)P
y
\sssi
7?2,5/5
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(R
(R4)p (R4)p 4)p
4 \
N(R )p
'=\ N N
N
0
(R4)p (R4) p k R4N
IP
S¨N N¨S S S NH
,,s1Nhs \z,N
or
0
HN). R4
)P
each R is independently hydrogen or an optionally substituted group selected
from C1,6 aliphatic,
a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring,
phenyl, an
8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or
partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic
ring having
1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an
8-10
membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur; or
two R groups are optionally taken together to form a bivalent C2-4 alkylene
chain;
two R groups are optionally taken together with their intervening atoms to
form an
optionally substituted 3-7-membered saturated or partially unsaturated
monocyclic ring
having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
each R' is independently hydrogen or a C1-3 aliphatic group optionally
substituted with halogen;
each of Rl is independently hydrogen, halogen, ¨CN, ¨NO2, ¨C(0)R, ¨C(0)0R,
¨C(0)NR2, ¨
C(0)NRS(0)2R, ¨C(0)N=S(0)R2, ¨NRz, ¨NRC(0)R, ¨NRC(0)NR2, ¨NRC(0)0R, ¨
NRS(0)2R, ¨NRS(0)2NR2, ¨OR, ¨0N(R)S02R, ¨P(0)R2, ¨SR, ¨S(0)R, ¨S(0)2R, ¨
S(0)(NH)R, ¨S(0)2N(R)2, ¨S(NH2)2(0)0H, ¨N=S(0)R2, -CH3, -CH2OH, -
CH2NHSO2CH3, ¨CD3, ¨CD2NRS(0)2R, or R; or:
two Rl groups are optionally taken together to form =0 or =NH; or
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two le groups are optionally taken together to form a bivalent C2-4 alkylene
chain;
each of R2 is independently hydrogen, halogen, ¨CN, ¨C(0)N(R')2, ¨OR',
¨N(R')2, ¨S(0)2R, ¨
S(0)2N(R)2, ¨0-phenyl, or an optionally substituted group selected from C1-3
aliphatic,
phenyl, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or 4-8 membered
saturated
monocyclic heterocycle having 1-4 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur;
R3 is hydrogen, halogen, ¨CN, ¨OR', ¨N(R')2, or an optionally substituted
group selected from
C1-3 aliphatic, phenyl, or a 5-6 membered monocyclic heteroaromatic ring
having 1-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R4 is hydrogen, halogen, ¨CN, ¨OR, ¨N=S(0)R2, ¨N(R)2, or an optionally
substituted group
selected from C1-3 aliphatic, a 4-8 membered saturated or partially
unsaturated monocyclic
heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen,
oxygen, or
sulfur, or a 7-12 membered saturated or partially unsaturated spirocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1, or 2;
p is 0 or 1; and
q is 0 or 1.
[0048] As defined above and described herein, Ring A is selected from a 3-8
membered
saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-
10 membered bicyclic
aromatic carbocyclic ring, a 4-8 membered partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur
optionally fused
to a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected
from nitrogen,
oxygen, or sulfur, a 7-12 membered partially unsaturated spirocyclic
heterocyclic ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12
membered partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bridged
bicyclic heterocyclic
ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 5-6
membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected from
CA 03089769 2020-07-27
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nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaromatic ring
having 1-5
heteroatoms independently selected from nitrogen, oxygen, or sulfur, or Het,
wherein Het is a 4-8
membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms
independently selected
from nitrogen, oxygen, or sulfur, a 7-12 membered saturated spirocyclic
heterocyclic ring having
1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-
12 membered
saturated bicyclic heterocyclic ring having 1-3 heteroatoms independently
selected from nitrogen,
oxygen, or sulfur, or a 7-12 membered saturated bridged bicyclic heterocyclic
ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0049] In some embodiments, Ring A is 3-8 membered saturated or partially
unsaturated
monocyclic carbocyclic ring. In some embodiments, Ring A is phenyl. In some
embodiments,
Ring A is an 8-10 membered bicyclic aromatic carbocyclic ring. In some
embodiments, Ring A
is a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-
2 heteroatoms
independently selected from nitrogen, oxygen, or sulfur optionally fused to a
5-6 membered
aromatic ring having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur. In
some embodiments, Ring A is a 7-12 membered partially unsaturated spirocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur. In some
embodiments, Ring A is a 7-12 membered partially unsaturated bicyclic
heterocyclic ring having
1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In
some embodiments,
Ring A is a 7-12 membered partially unsaturated bridged bicyclic heterocyclic
ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some
embodiments, Ring
A is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms
independently
selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is an 8-
10 membered
bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected
from nitrogen,
oxygen, or sulfur.
[0050] In some embodiments, Ring A is Het. In some embodiments, Ring A is a
4-8
membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms
independently selected
from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 7-12
membered saturated
spirocyclic heterocyclic ring having 1-4 heteroatoms independently selected
from nitrogen,
oxygen, or sulfur. In some embodiments, Ring A is a 7-12 membered saturated
bicyclic
heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur.
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In some embodiments, Ring A is a 7-12 membered saturated bridged bicyclic
heterocyclic ring
haying 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
AN'\
[0051] In some embodiments, Ring A is
(R )m . In some embodiments, Ring A is
"js-N----\
N "cc
M\1 ¨(R 1
6
(R16. In some embodiments, Ring A is
. In some embodiments, Ring
ssrc
/
¨(R16
> M\1
N 1
A is . In some embodiments, Ring A is
. In some embodiments,
1 1 1
Ring A is N . In some embodiments, Ring A is
. In some
\ N.AjN
embodiments, Ring A is (R1)rn . In some embodiments, Ring A is
(Ri)rn . In some
si&Nir
(R16
1 ,N
N 1
embodiments, Ring A is N . In some embodiments, Ring A is
(Ri)rn . In some
sss.' sssL
N 1 N 1
embodiments, Ring A is O
. In some embodiments, Ring A is s
. In
-ss&NV
[ 9
(R)õ
1
some embodiments, Ring A is (Ri)rn . In some embodiments, Ring A is
. In
I I
---X
some embodiments, Ring A is . In some embodiments, Ring A is
(R1)m .
22
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ss<Ni...9 _________________________________________ (W)rii
[0052] In some embodiments, Ring A is
. In some embodiments, Ring
(R1)rn
sj41)m
jsPr<NLJO
A is . In some embodiments, Ring A is
. In some embodiments,
.4_
53.< NI,b(R1 ) m
Ring A is (R1),. In some
embodiments, Ring A is . In some
H
1 N
i--N 1 (R1),
\--- 7
¨ 0
embodiments, Ring A is R .
In some embodiments, Ring A is
is<NLR1),õ
sssC-' 6iN (R1 a
),,
. In some embodiments, Ring A is
. In some embodiments,
5555sN. /N1
LK
*0
Ring A is (R1)rn
. In some embodiments, Ring A is (R1)rn . In some embodiments,
s&NyiAN
Ring A is (R1)m . In some embodiments, Ring A is
(R1)m. In some embodiments,
AN ¨N N
j ss4N
Ring A is (R1)m. In some embodiments, Ring A is
. In some
N 1
is- Ci_7-(R )m
I N
embodiments, Ring A is 0 .
In some embodiments, Ring A is
N
___________ (R1)rn sss( _____ (R1)m
ss4N) N
0
. In some embodiments, Ring A is N
. In some
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I
(R1)m
iNrN
sis(N-'1.\n
N.-..../¨
embodiments, Ring A is N (R1)m . In
some embodiments, Ring A is .
AN scs(N
cNI___)
cN)
/--N
/
In some embodiments, Ring A is (R1)m . In
some embodiments, Ring A is .. (R1),, In
ss(N
N,
¨1(R1),
some embodiments, Ring A is
. In some embodiments, Ring A is
sjs( ? 1 sr(N
/(R),õ
7 1\1N
N . In some embodiments, Ring A is
(R1)m . In some embodiments,
ss-(N (R1),,-,
1\1)\0
N-....1)
Ring A is (R1)m . In some embodiments, Ring A is
. In some
(R1),,
ss<N>(
sri(N ,c_31
embodiments, Ring A is N11---/ (R1)m . In some embodiments, Ring A is
N
. In some embodiments, Ring A is (R 1, )
m . In some embodiments, Ring A is
(FV)m
ss<N /6-(R1),
c_N__1
. In some embodiments, Ring A is . In some embodiments,
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(R1)m
#41\1(R1)m ss(NLN
Ring A is H. In some embodiments, Ring A is
. In some
(R1),,
ANX sskNO
\JN
7
embodiments, Ring A is 0. In some embodiments, Ring A is (R )m
I N
[0053] In some embodiments, Ring A is
N. In some embodiments, Ring A is
µ2Z,
N (R1)m
(R )m. In some embodiments, Ring A is
. In some embodiments, Ring
=P'NQ ______________________________________________ srs<ir (R1),,
A is (R1)m . In some embodiments, Ring A is
. In some embodiments,
Ring A is (Ri)rn . In some embodiments, Ring A is
(Ri)rn . In some
embodiments, Ring A is (R1)m
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ss-N (R16
---)
[0054] In some embodiments, Ring A is
N . In some embodiments, Ring A is
3s.N
. In some embodiments, Ring A is
. In some embodiments, Ring
ss<N sj<N
N \1\1)
N111 Iti\iFi
A is (Ri)rn . In some embodiments, Ring A
is (Ri)m .
ssCN(R1),,,
[0055] In some embodiments, Ring A is 0
. In some embodiments, Ring A is
\-N
(Ri)m . In some embodiments, Ring A is
(Ri)m . In some embodiments, Ring
ss&N Na
A is (R1)m .
is<N] (R16
I /
' I
[0056] In some embodiments, Ring A is
N. In some embodiments, Ring A is
ss<N
XN¨LR1)rn I IA
1 / ,
I
0 . In some embodiments, Ring A is
(R1)rn . In some embodiments, Ring A
/
N¨
ss< la
N
is I P(R1)m. In some embodiments, Ring
A is (R1)rn . In some embodiments,
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N¨ N¨
I
r----\ N
Ring A is _..--N . In some embodiments,
Ring A is 0 kr.µ)m,,i, . In some
AN N
(R1),,
embodiments, Ring A is .
In some embodiments, Ring A is
AN (R1) i
NNOC 1
,, H¨(R 6
N N
. In some embodiments, Ring A is
. In some
i
NNLX, (Ri)m
embodiments, Ring A is N .
In some embodiments, Ring A is
A
NO<>\
1 AN0.0_(R16
(R)m. In some embodiments, Ring A is
. In some
N N
sANOC )
iNN (R1), \
embodiments, Ring A is . In some embodiments, Ring A is
(R1)m.
A
\
NO( 0
\ /
In some embodiments, Ring A is
(Ri)rn . In some embodiments, Ring A is
R1 (R1),,,
)ni
ANOC7)( SS5S(NLy 1 \
N
N . In some embodiments, Ring A is
/ . In some embodiments,
N (R1),,
N
Ring A is (Ri)m . In some embodiments, Ring A is
. In some embodiments,
AN (R1),,,
N(R1)
Ring A is
V . In some embodiments, Ring A is Am. In some
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AN
7
N
embodiments, Ring A is . In some embodiments, Ring A is
. In
sr<N
(R1,
.ss ),
N
0
some embodiments, Ring A is . In some
embodiments, Ring A is (R1), .
(R1),,
ss&N-7-N7
In some embodiments, Ring A is
. In some embodiments, Ring A is
ANi 1
(R )m I (R1)m
. In some embodiments, Ring A is (:) . In some embodiments,
(R16
''sTh\l
`AN
(R1)m
Ring A is . In some embodiments, Ring A is 0
. In some
(R1),
AN 0
embodiments, Ring A is . In some
embodiments, Ring A is (Ri)m . In some
(R1)m
AN (R1),õ
e-N ss(N
0
embodiments, Ring A is `' . In some embodiments, Ring A is
. In some
(R'),õ
QI (R16
ss5(N N AN
embodiments, Ring A is . In some embodiments, Ring A is
. In
(R1),
ss(N
C:)\
some embodiments, Ring A is J .
In some embodiments, Ring A is
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ss(Nv\ (R 1)m
')m
AN F----\1
N (R1)õ,
. In some embodiments, Ring A is \vN . In some embodiments,
k N v\
N N ,
,m
Ring A is k'ihn . In some embodiments, Ring A is 0
. In some
7>--(R1)
/NN
embodiments, Ring A is 0
. In some embodiments, Ring A is
1 VN 1 713 i
s' 'N (R )1'1 ss.4N (R ),
N
. In some embodiments, Ring A is
. In some
(R1),,
is&N 0
1 04\
N 1Th\l/N
embodiments, Ring A is (R1)õ . In some embodiments, Ring A is
[0057] In some embodiments, Ring A is selected from those depicted in Table
1, below.
(R4)p (R4)p
- N
N/ /
1 I
\,(Ns, l'1,(Nssi
[0058] As defined above and described herein, Ring B is
,
(R4 )p tpc4 \IP (R4)p
AR 4)p "
NN f N N (R4)
/1
I ) 13 I I I
41ZZZ, \ / µ2,siS '112s,
/
(R4)p (R4)p \ (R4)
(R4)
p
p
IM4N
-CINI +1 NV N
I 1 I I
le,,./ ''2,ese \N 't1, N
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0
(R4)p (17e1)13 (Fel)
S¨N N¨S S S N H
' z,,,,A - -I '' '\- - -ssi ' ?z( 0 /
N N N N ,,I is,
, or
,
0
HN7.-1,(R4)
----- P
(R4)p
- N
1 I
i \ z,, N I
[0059] In some embodiments, Ring B s
. In some embodiments, Ring B is
(R4)p (R4)p
/ N N
N/ k I
1
s'. . In some embodiments, Ring B is
/ . In some embodiments, Ring
(R4)
l p
X
/(R4)p N
I
B is \ kr /
. In some embodiments, Ring B is \-s" . In some embodiments,
AR 4)p (R4)p
N.
I
Ring B is \r,..-........õ,.....4
sr . In some embodiments, Ring B is \
/ . In some
(R4)p (R4)p
ri \ 11
)
embodiments, Ring B is \,./ss . In some embodiments, Ring B is
. In
N(R4)p
1
< 1\11
some embodiments, Ring B is
. In some embodiments, Ring B is
CA 03089769 2020-07-27
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(R4)p
(R4)p
N
. In some embodiments, Ring B is
. In some embodiments,
S¨N
Ring B is I. In some embodiments, Ring B is
. In some
(R4)p (R4)p
"z2zrOss,
embodiments, Ring B is . In some embodiments, Ring B is
. In
0
(R4)NH
,,
some embodiments, Ring B is
I . In some embodiments, Ring B is
0
HN7
\
=
[0060] In
some embodiments, Ring B is selected from those depicted in Table 1, below.
[0061]
As defined above and described herein, each R is independently hydrogen or an
optionally substituted group selected from C1.6 aliphatic, a 3-8 membered
saturated or partially
unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic
aromatic carbocyclic
ring, a 4-8 membered saturated or partially unsaturated monocyclic
heterocyclic ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6
membered monocyclic
heteroaromatic ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, or
sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5
heteroatoms independently
selected from nitrogen, oxygen, or sulfur; or two R groups are optionally
taken together to form a
bivalent C2-4 alkylene chain; or two R groups are optionally taken together
with their intervening
atoms to form an optionally substituted 3-7-membered saturated or partially
unsaturated
monocyclic ring having 0-4 heteroatoms independently selected from nitrogen,
oxygen or sulfur.
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[0062] In some embodiments R is hydrogen. In some embodiments R is an
optionally
substituted C1-6 aliphatic group. In some embodiments R is an optionally
substituted 3-8
membered saturated or partially unsaturated monocyclic carbocyclic ring. In
some embodiments
R is an optionally substituted phenyl. In some embodiments R is an optionally
substituted 8-10
membered bicyclic aromatic carbocyclic ring. In some embodiments R is an
optionally substituted
4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some
embodiments R is
an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-
4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. In some embodiments R
is an optionally
substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms
independently
selected from nitrogen, oxygen, or sulfur. In some embodiments two R groups
are optionally taken
together to form a bivalent C2-4 alkylene chain. In some embodiments two R
groups are optionally
taken together with their intervening atoms to form an optionally substituted
3-7-membered
saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms
independently selected
from nitrogen, oxygen or sulfur.
[0063] In some embodiments, R is selected from those depicted in Table 1,
below.
[0064] As defined above and described herein, each of R' is independently
hydrogen or a Cl-
3 aliphatic group optionally substituted with halogen.
[0065] In some embodiments, R' is hydrogen. In some embodiments, R' is a C1-
3 aliphatic
group optionally substituted with halogen.
[0066] In some embodiments, R' is selected from those depicted in Table 1,
below.
[0067] As defined above and described herein, each of le is independently
hydrogen, halogen,
¨CN, ¨NO2, ¨C(0)R, ¨C(0)0R, ¨C(0)NR2, ¨C(0)NRS(0)2R, ¨C(0)N=S(0)R2, ¨NR2, ¨
NRC (0)R, ¨NRC (0)NR2, ¨NRC (0)0R, ¨NRS (0)2R, ¨NRS (0)2NR2, ¨OR, ¨0N(R)S 02R,
¨
P(0)R2, ¨SR, ¨S(0)R, ¨S(0)2R, ¨S(0)(NH)R, ¨S(0)2N(R)2, ¨S(NH2)2(0)0H,
¨N=S(0)R2, -CH3,
-CH2OH, -CH2NHSO2CH3, ¨CD3, ¨CD2NRS(0)2R, or R; or: two RI- groups are
optionally taken
together to form =0 or =NH; or two le groups are optionally taken together to
form a bivalent C2-
4 alkylene chain.
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[0068]
In some embodiments, le is hydrogen. In some embodiments, le is halogen. In
some
embodiments, le is ¨CN. In some embodiments, le is ¨NO2. In some embodiments,
le is ¨
C(0)R. In some embodiments, le is ¨C(0)0R. In some embodiments, le is
¨C(0)NR2. In some
embodiments, le is ¨C(0)NRS(0)2R. In some embodiments, le is ¨C(0)N=S(0)R2. In
some
embodiments, le is ¨NR2. In some embodiments, le is ¨NRC(0)R. In some
embodiments, le is
¨NRC(0)NR2. In some embodiments, le is ¨NRC(0)0R. In some embodiments, le is ¨
NRS(0)2R. In some embodiments, le is ¨NRS(0)2NR2. In some embodiments, le is
¨OR. In
some embodiments, le is ¨0N(R)S02R. In some embodiments, le is ¨P(0)R2. In
some
embodiments, le is ¨SR. In some embodiments, le is ¨S(0)R. In some
embodiments, le is ¨
S(0)2R. In some embodiments, le is ¨S(0)(NH)R. In some embodiments, le is
¨S(0)2N(R)2. In
some embodiments, le is ¨S(NH2)2(0)0H. In some embodiments, le is ¨N=S(0)R2.
In some
embodiments, le is ¨CD3. In some embodiments, le is ¨CD2NRS(0)2R. In some
embodiments,
R' is R. In some embodiments, two le groups are optionally taken together to
form =0 or =NH.
In some embodiments, two le groups are optionally taken together to form a
bivalent C2-4 alkylene
chain.
[0069]
In some embodiments, le is fluoro. In some embodiments, le is chloro. In some
embodiments, le is methyl. In some embodiments, le is ethyl. In some
embodiments, le is ¨OH.
In some embodiments, le is ¨OCH3. In some embodiments, le is ¨CH2OH. In some
embodiments, le is ¨CH2CN. In some embodiments, le is ¨CF3. In some
embodiments, le is ¨
CH2NH2. In some embodiments, le is ¨COOH. In some embodiments, le is ¨NH2.
[0070]
In some embodiments, two le groups form =0. In some embodiments, two le groups
form =NH. In some embodiments, two le groups form -,'N" .
[0071] In some embodiments, le is In some embodiments, le is
In some
embodiments, le is
V . In some embodiments, le is \V< . In some embodiments, le
OH OH
OH
is . In some embodiments, le is
In some embodiments, le is \.). In
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F NH2
some embodiments, le is \.)F . In some embodiments, le is µ.\) . In some
embodiments,
CF3
R' is 4)N H2
[0072] In some embodiments, le is . In some embodiments, le is
. In
some embodiments, R1 is 8 . In some embodiments, R1 is
0 0 . In some
=-t,<OH
embodiments, le is 0H . In some embodiments, le is
. In some
NH2 .CN
embodiments, le is . In some embodiments, le is
. In some
0
embodiments, le is '(*(). In some embodiments, le is Ao .
00
\\I,
S
[0073] In some
embodiments, le is µ20H . In some embodiments, le is
0 NH 0
II
S
'22
. In some embodiments, le is . In some embodiments, le is
. In some
0
H2N,H
0 S¨NH2
/
embodiments, le is '11'.L <. In some embodiments, le is \ 6F1
. In some
0 F 1
NT'
N
\c
embodiments, le is F . In some embodiments, R1 is
. In some embodiments, le
0, NH
vo
'?yS
is
H . In some embodiments, le is ?4
=
,s 0.µ / i (:)µµ /
ss,.. s
[0074] In some embodiments, le is
W . In some embodiments, le is s'The. In
0µ /
i 0 K
sNS _____________________________________________________________
s-
some embodiments, le is N . In some embodiments, le is
V. In some
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0
õµ \ S
embodiments, le is / NSO . In some embodiments, le is YLN
. In some
0 0õ0 µµ,0,
N
embodiments, le is '2, NH2. In some embodiments, le is
H . In some embodiments,
(R,\/ 0_0
R' is 2re. In some embodiments, le is
0, D 0õ0
Vq Vg
V 1\l'S VI\l'S
[0075] In some embodiments, R1 is H . In some embodiments, R1 is
H .
,zz(\ 0µ\ P 00
,s V`N-s
N
In some embodiments, le is H . In some embodiments, le is I
. In some
\-7 0 0 D D 0õ0
\\ /,
VCN-S \z)(N/S
embodiments, le is H . In some embodiments, le is H
. In some
00 00
\\ //
\z71\l'SCF3
embodiments, le is H . In some embodiments,
le is H . In some
0õ0
\\ I,
\N
0 'S
,
v /,NH
'z%7N-S 0
embodiments, le is H . In some embodiments, le is NMe2 .
00
\\/,
'''Cl\l'S'srl
[0076] In some embodiments, le is H
\--NH . In some embodiments, le is
0 0 0õ0
'''rN'S'sc-1 ssk ,S
H \---0 . In some embodiments, le is HN
¨O.\ In some embodiments, le is
sKN,S,r_l sN'S
H \--NH . In some embodiments, le is
H . In some embodiments, le is
CA 03089769 2020-07-27
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0õ0 00
00
\\ /, \\ /,
siNN,S ssk ,s sskN
. ,s.õ
H . In some embodiments, le is 11 V. In
some embodiments, le is H
00 \ , 'f), 0 0
\ /
sskN'S \z2N-S
. In some embodiments, le is I . In some embodiments, le is H .
0
0
A
[0077] In some embodiments, le is 't NH2 . In some embodiments, le is
H . In
0
0
.,)"
some embodiments, le is `1.
. In some embodiments, le is . In some embodiments,
0
0
-L,_)-CN
R1 is -L, . In some embodiments, le is H
. In some embodiments, le is
\
0 0
ON
II
\-,
H . In some embodiments, le is I . In some embodiments, le is
H .
(i)
In some embodiments, le is
0 0, NH
µ,
/,
[0078]
In some embodiments, le is es . In some embodiments, le is csCS . In
0õ0
00 v ,,
i/.........,S,N
some embodiments, le is cs'S'NF12 . In some embodiments, le is
H . In some
0
.,..õ,NH2
AN)
embodiments, le is 0 . In some embodiments, le is
H . In some embodiments,
0 0 0
\rN'S'Nv 1\1 N
Itl is H H . In some embodiments, le is
H H . In some embodiments, le is
Rp Rp
NN H2 AN,\Si,N
H . In some embodiments, le is H H .
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00
\\ I,
NH2
[0079] In some embodiments, le is
. In some embodiments, le is
0 0 H
ssi<NNH2 issNSO2Me
H . In some embodiments, le is
H . In some embodiments, le is
00 00
\\ //
H . In some embodiments, le is
H . In some embodiments, le is
0\µ P 0õ0
Vg
1 YNNS NH2
OH . In some embodiments, le is H
. In some embodiments, le is
00 00
\\* \\ /,
'zz(N/S'N ''N'S'NH2
H I . In some embodiments, le is I
. In some embodiments, le is
0
µ.(NANH2
H
=
0 0
µzz(N) n)õ,
[0080] In some embodiments, le is H . In some embodiments, le is
,1,,NH2 0
.0
. In some embodiments, le is 0 . In some embodiments, R1 is
. In some
0 0
embodiments, R1 is . In some
embodiments, R1 is `z= NH2. In some
H
0 0 1r0
embodiments, le is NH2. In some embodiments, le is 0
. In some
0 0, ,0
, f,
embodiments, le is NFI . In some embodiments, le is 0 .
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0
S,
\ N N
[0081] In some embodiments, le is H . In some embodiments, le is \
1----r
HN ___________________________ Cr .1,,_/ \::.-.--N
. In some embodiments, le is ' N . In some embodiments, le is -',-
. In
N,n
some embodiments, le is
N . In some embodiments, le is r \---1. In some
\J:7) embodiments, le is . In some
embodiments, le is . In some embodiments,
IN tN
R1 is OF1 . In some embodiments, le is NH
=
IN iTh\I
[0082] In some embodiments, le is . In some
embodiments, le is NSO2Me
0
1( N
. -NANH
In some embodiments, is N. In some embodiments, is 1"
R' le \----/ . In some
0
V\.V\embodiments, le is 1 0 i R' . In some
embodiments, s . In some embodiments, le
is")::.3,H /C)s
i le \--N>-F le \ 0
0s . In some embodiments, is . In
some embodiments, is =
OH
In some embodiments, le is \
Nri
38
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.......FH r\i1H
N N
[0083] In some embodiments, le is . In some
embodiments, le is OH . In
1\11H i _____ cr\iiH
N
N
some embodiments, le is . In some embodiments, le is CF3
In some
IN,JH
i _____________________ cr 5 N
--N
embodiments, le is NC . In some embodiments, le is
. In some embodiments,
cr
c1\11H
--N
CH - N
R1 is CI . In some embodiments, le is 'N . In some embodiments, le is
cr
5 --N
. In some embodiments, le is F .
H2N
,,,(cZ) H
N-1\1,
NH I õN
,
N N
[0084] In some embodiments, le is . In some
embodiments, le is . In
OH OH
---c-1,--
-NH .
some embodiments, le is `N-NH
. In some embodiments, le is \N
In
/
\--OH -NH . some embodiments, le is . In some
embodiments, le is \N In some
/ /----
___CNII 1____CNII
embodiments, le is ' N . In some embodiments, le is N
. In some embodiments,
1---
R1 is N NH . In some embodiments, le is hfir" .
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1
? _______________________________ N-N
[0085] In some embodiments, le is
/ . In some embodiments, le is rN\-----. In some
NH2 CF3
1--NIN
embodiments, le is N . In some embodiments, le is
. In some
Nr----)
-/S,
\N
embodiments, le is N . In some embodiments, le is
d \ . In some embodiments,
0 0
,XNH `z2( NH
AR' is . In some embodiments, le is
. In some embodiments, le is
...----..õ.0
N \NC)
NH NH
. In some embodiments, le is .
,zz(CiNH
vC
[0086] In some embodiments, le is . In some embodiments, le is
NH. In
C0
<-4 NH v some embodiments, le is -'? . In some
embodiments, le is . In some
0
\rN VTho
embodiments, le is (:) . In some embodiments, le is
. In some
OH
embodiments, le is
\CO el
. In some embodiments, le is ''11\11-3 . In some
H
L ),,
embodiments, le is . In some embodiments, le is NI .
rN----
1 N
[0087] In some embodiments, le is N-=--/ . In some embodiments, R1 is
N 1.,___/ .
In some embodiments, le is N'"--1 . In some embodiments, le is
NN. In some
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N
r_N\
Z NI --)¨CF3
N
embodiments, le is \ . In some embodiments, le is
. In some embodiments,
H
CF3 N--,
1 II ____________________________ ,NH
N
R1 is hCCH . In some embodiments, le is N-N . In some embodiments, le is
-NI
N,T,õCF3
. In some embodiments, le is
S
,v{
N CY
[0088] In some embodiments, le is . In some
embodiments, le is N= In
sm 1101
some embodiments, le is K___
' N . In some embodiments, le is
. In some
I
'zzz(N
embodiments, le is . In some embodiments, le is 1,
. In some embodiments,
VN
1
t2z,N ,z2,7-
le is 'z2, . In some embodiments, le is '-
'2, . In some embodiments, le is
0
H
N
N
1 . In some embodiments, le is N-NH =
N
NCI
__________________________________ /
[0089] In some embodiments, le is µ-NH . In
some embodiments, le is 1 NIF1 .
zN,.....< N
/
In some embodiments, le is µ-NFI . In some embodiments, le is H=µ-N
In some
;6--OH
H
N
H
embodiments, le is N-N. In some embodiments, le is µ
. In some embodiments,
41
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/LN2 N- 01
\
R' is \ . In some embodiments, le is \ . In
some embodiments, le is '', . In
H
N/
1 II
some embodiments, le is N-N .
\
Nõ....õ:õ,0F3 F_Nii
U
[0090] In some embodiments, R1 is H . In
some embodiments, le is .
H
N-NH S
In some embodiments, le is
N0 . In some embodiments, le is ni\ls -N . In some
S
3 0,
1 I,
embodiments, le is K N . In some embodiments, le is -
---1\1 . In some embodiments, le
0, 0
is i N . In some
embodiments, R1 is ' N-N . In some embodiments, R1 is N .
0-Th/ N4
1--- li
Yz, /N
[0091] In some embodiments, le is
N-N . In some embodiments, le is 0 . In
/
0 r-NH 0 r-N
some embodiments, R1 is H . In some embodiments, R1 is H .
0
,2z(val
[0092] In some embodiments, le is F-X-3 . In some embodiments, le is
.
I
0
OH
In some embodiments, Rl is . In some embodiments, Rl is
OH
. In some
N,
51_ 0
-N -N
embodiments, le is 0 . In some embodiments, le is
. In some embodiments, le
42
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00
rr
s . In some embodiments, le is
. In some embodiments, le is
'11<*y0H
OH
=
[0093] In some embodiments, le is selected from those depicted in Table 1,
below.
[0094]
As defined above and described herein, each of R2 is each of R2 is
independently
hydrogen, halogen, ¨CN, ¨C(0)N(R')2, ¨OR', ¨N(R')2, ¨S(0)2R, ¨S(0)2N(R)2, ¨0-
phenyl, or an
optionally substituted group selected from C1-3 aliphatic, phenyl, 5-6
membered monocyclic
heteroaromatic ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, or
sulfur, or 4-8 membered saturated monocyclic heterocycle having 1-4
heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
[0095]
In some embodiments, R2 is hydrogen. In some embodiments, R2 is halogen. In
some
embodiments, R2 is ¨CN. In some embodiments, R2 is ¨C(0)N(R')2. In some
embodiments, R2
is ¨OR'. In some embodiments, R2 is ¨N(R')2. In some embodiments, R2 is
¨S(0)2R. In some
embodiments, R2 is ¨S(0)2N(R)2. In some embodiments, R2 is ¨0-phenyl. In some
embodiments,
R2 is an optionally substituted C1-3 aliphatic group. In some embodiments, R2
is an optionally
substituted phenyl. In some embodiments, R2 is an optionally substituted 5-6
membered
monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected
from nitrogen,
oxygen, or sulfur. In some embodiments, R2 is an optionally substituted 4-8
membered saturated
monocyclic heterocycle having 1-4 heteroatoms independently selected from
nitrogen, oxygen, or
sulfur.
[0096]
In some embodiments, R2 is fluoro. In some embodiments, R2 is chloro. In some
embodiments, R2 is bromo. In some embodiments, R2 is methyl. In some
embodiments, R2 is
ethyl. In some embodiments, R2 is ¨CF3. In some embodiments, R2 is
. In some
\/ `=%
embodiments, R2 is . In some embodiments, R2 is
H . In some embodiments, R2 is
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F OH
µ%,
[0097] In some embodiments, R2 is 4.1\-)F . In some embodiments, R2 is ca
. In some
F
"( () `=
embodiments, R2 is 0 F= In some embodiments, R2 is 'z
. In some embodiments, R2
H 0 0
YL- YL
is '', . In some embodiments, R2 OH is . In
some embodiments, R2 NH is 2. In
0 0
Y.'N \N
some embodiments, R2 is H . In some
embodiments, R2 is I . In some
_.---:-- \-
NH
Nr3
embodiments, R2 is . In some embodiments, R2 is 't
. In some embodiments,
F
rj-F
N
R2is =
/ H
,N ,N
4.1<i[0098] In some
embodiments, R2 is -(S \ . In some embodiments, R2 is . In
n
some embodiments, R2 is N . In some
embodiments, R2 is . In some
IN
I
401
/
embodiments, R2 is . In some embodiments, R2 is
. In some embodiments, R2
NC s
140
is . In some embodiments, R2 is
OH. In some embodiments, R2 is
0 OH
H . In some embodiments, R2 is .
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110
[0099] In some embodiments, R2 is
. In some embodiments, R2 is
0
VQA
NH2 N
01
0
. In some embodiments, R2 is
=
[00100] In some embodiments, R2 is selected from those depicted in Table 1,
below.
[00101] As defined above and described herein, R3 is hydrogen, halogen, ¨CN,
¨OR', ¨N(R')2,
or an optionally substituted group selected from C1-3 aliphatic, phenyl, or a
5-6 membered
monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected
from nitrogen,
oxygen, or sulfur.
[00102] In some embodiments, R3 is hydrogen. In some embodiments, R3 is
halogen. In some
embodiments, R3 is ¨CN. In some embodiments, R3 is ¨OR'. In some embodiments,
R3 is ¨
N(R')2. In some embodiments, R3 is an optionally substituted C1-3 aliphatic
group. In some
embodiments, R3 is an optionally substituted phenyl. In some embodiments, R3
is an optionally
substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms
independently
selected from nitrogen, oxygen, or sulfur.
[00103] In some embodiments, R3 is selected from those depicted in Table 1,
below.
[00104] As defined above and described herein, R4 is hydrogen, halogen, ¨CN,
¨OR, ¨
N=S(0)R2, ¨N(R)2, or an optionally substituted group selected from C1-3
aliphatic, a 4-8 membered
saturated or partially unsaturated monocyclic heterocyclic ring having 1-2
heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered
saturated or partially
unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, or sulfur.
[00105] In some embodiments, R4 is hydrogen. In some embodiments, R4 is
halogen. In some
embodiments, R4 is ¨CN. In some embodiments, R4 is ¨OR. In some embodiments,
R4 is ¨
N=S(0)R2. In some embodiments, R4 is ¨N(R)2. In some embodiments, R4 is an
optionally
substituted C1-3 aliphatic group. In some embodiments, R4 is an optionally
substituted 4-8
membered saturated or partially unsaturated monocyclic heterocyclic ring
having 1-2 heteroatoms
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independently selected from nitrogen, oxygen, or sulfur. In some embodiments,
R4 is an optionally
substituted 7-12 membered saturated or partially unsaturated spirocyclic
heterocyclic ring having
1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00106] In some embodiments, R4 is fluoro. In some embodiments, R4 is chloro.
In some
embodiments, R4 is methyl. In some embodiments, R4 is ¨CF3. In some
embodiments, R4 is ¨
OH. In some embodiments, R4 is \ . In some embodiments, R4 is \
. In some
OH ,22(1\1s0
embodiments, R4 is . In some
embodiments, R4 is . In some
embodiments, R4 is '2'
[00107] In some embodiments, R4 is H . In some embodiments, R4 is
C\NH
rNH2
. In some embodiments, R4 is . In some embodiments, R4 is
In some
1¨N 0
embodiments, R4 is . In some embodiments, R4 is
. In some
F
-N NH NH
embodiments, R4 is . In some embodiments, R4 is
. In some
HN
FNV FNOXN
embodiments, R4 is . In some embodiments, R4 is
0
FNXN--c
[00108] In some embodiments, R4 is
. In some embodiments, R4 is
FNOXOO FN<C>
. In some embodiments, R4 is
[00109] In some embodiments, R4 is selected from those depicted in Table 1,
below.
[00110] As defined above and
described herein, m is 0, 1, 2, 3, 4 or 5.
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[00111] In some embodiments, m is 0. In some embodiments, m is 1. In some
embodiments,
m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some
embodiments, m is
5.
[00112] In some embodiments, m is 1, 2 or 3.
[00113] In some embodiments, m is selected from those depicted in Table 1,
below.
[00114] As defined above and described herein, n is 0, 1, or 2.
[00115] In some embodiments, n is 0. In some embodiments, n is 1. In some
embodiments, n
is 2.
[00116] In some embodiments, n is selected from those depicted in Table 1,
below.
[00117] As defined above and described herein, p is 0 or 1.
[00118] In some embodiments, p is 0. In some embodiments, p is 1.
[00119] In some embodiments, p is selected from those depicted in Table 1,
below.
[00120] As defined above and described herein, q is 0 or 1.
[00121] In some embodiments, q is 0. In some embodiments, q is 1.
[00122] In some embodiments, q is selected from those depicted in Table 1,
below.
[00123] In certain embodiments, the present invention provides a compound of
formula I,
wherein Ring A is Het, thereby forming a compound of formula II:
(RN
(R3)q
N1N (Ri)m
or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R2,
R3, ¨ 4,
K m, n, p, and
q is as defined above and described in embodiments herein, both singly and in
combination.
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[00124] In certain embodiments, the present invention provides a compound of
formula I,
(R4)p
wherein Ring A is Het and Ring B is
, thereby forming a compound of formula
(R4)p
("c
N N
= (R1)III
1N
or a pharmaceutically acceptable salt thereof, wherein each of Het, le, R2,
R3, -rs4,
K m, n, p, and q
is as defined above and described in embodiments herein, both singly and in
combination.
[00125] In certain embodiments, the present invention provides a compound of
formula I,
(R4) p
wherein Ring A is piperidinyl, piperazinyl, or morpholinyl, and Ring B is
thereby forming a compound of formula IV-a, IV-b, or IV-c, respectively:
(R4)p (R4)
P
3 3 N\
N N
N
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IV-a IV-b
(R4)p
1\\
(R3) (R1)n,
_
N N
I
0
0¨(R2)n
IV-c
or a pharmaceutically acceptable salt thereof, wherein each of 10, R2, R3, ¨4,
K m, n, p, and q is as
defined above and described in embodiments herein, both singly and in
combination.
[00126] In certain embodiments, the present invention provides a compound of
formula I,
(R4)p
N N
wherein Ring A is Het and Ring B is 1 , thereby forming a compound
of formula
V:
(R4)p
(R3)q N\''N
N (R1)m
1N
0---(R2)11
V
or a pharmaceutically acceptable salt thereof, wherein each of Het, 10, R2,
R3, -rs4,
K m, n, p, and q
is as defined above and described in embodiments herein, both singly and in
combination.
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[00127] In certain embodiments, the present invention provides a compound of
formula I,
(R4)NkN
wherein Ring A is piperidinyl, piperazinyl, or morpholinyl, and Ring B is \
thereby forming a compound of formula VI-a, VI-b, or VI-c, respectively:
(R4)
(R4)p
r,\P
(R' )m
(R3)c),y()NL (R1)m
NNCI N N
cN
0¨(R2)n
VI-a VI-b
(R4)p
(RN 1),I)tNL
'
N
VI-c
or a pharmaceutically acceptable salt thereof, wherein each of le, R2, R3, ¨
4,
K m, n, p, and q is as
defined above and described in embodiments herein, both singly and in
combination.
[00128] In certain embodiments, the present invention provides a compound of
formula I,
(R4)p
f)
wherein Ring A is Het and Ring B N
, thereby forming a compound of formula
VII:
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(R4)p
(RN I
NN (R1),,
VII
or a pharmaceutically acceptable salt thereof, wherein each of Het,
R2, R3, R4, m, n, p, and q
is as defined above and described in embodiments herein, both singly and in
combination.
[00129] In certain embodiments, the present invention provides a compound of
formula I,
4
f R) p
)
wherein Ring A is piperidinyl, piperazinyl, or morpholinyl, and Ring B is N
thereby forming a compound of formula VIII-a, VIII-b, or VHI-c, respectively:
(R4)p
(R4)p
(R3)q (R3)q (R1)m
N NOV N N (R1)m
LN
0----(R2)n
VIII-a VIII-b
(R4)p
(RN 16 (R1
N N
0-(R2)r,
VIII-c
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or a pharmaceutically acceptable salt thereof, wherein each of le, R2, R3, ¨4,
K m, n, p, and q is as
defined above and described in embodiments herein, both singly and in
combination.
[00130] In certain embodiments, the present invention provides a compound of
formula I,
(R4)p
wherein Ring A is Het and Ring B is 72'
, thereby forming a compound of formula
IX:
(R4)p
N
(R3)q
(R1)Ix
or a pharmaceutically acceptable salt thereof, wherein each of Het, le, R2,
R3, -rs4,
K m, n, p, and q
is as defined above and described in embodiments herein, both singly and in
combination.
[00131] In certain embodiments, the present invention provides a compound of
formula I,
(R4)p
wherein Ring A is piperidinyl, piperazinyl, or morpholinyl, and Ring B is -
51 , thereby
forming a compound of formula X-a, X-b, or X-c, respectively:
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(p
(R4) R4)
p
\\
(RN v(Rril
(RN (R )m 1)
' N 1
X-a X-b
(R4)p
\\
(R3)q 1\1 (R1)m
N N1()
X-c
, R3, R4,
or a pharmaceutically acceptable salt thereof, wherein each of le, R2
m, n, p, and q is as
defined above and described in embodiments herein, both singly and in
combination.
[00132] In certain embodiments, the present invention provides a compound of
formula I,
(R4)p
wherein Ring A is Het and Ring B is
, thereby forming a compound of formula
XI:
(Fe)p
(R3)q N
I
)1,N
= (R1)m
XI
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or a pharmaceutically acceptable salt thereof, wherein each of Het, R1, R2,
R3, -rs4,
K m, n, p, and q
is as defined above and described in embodiments herein, both singly and in
combination.
[00133] In certain embodiments, the present invention provides a compound of
formula I,
(R4)p
'''erNs
wherein Ring A is piperidinyl, piperazinyl, or morpholinyl, and Ring B is
j , thereby
forming a compound of formula XII-a, XII-b, or XII-c, respectively:
(R4)p (R4)p
\N
(R3)q N (R3)q (R1)m
(R1)m
/
)1VN N N /1
N1N
XII-a XII-b
(R4)p
\\
q A
N N 1
Nn
xll_c
or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, ¨4,
K m, n, p, and q is as
defined above and described in embodiments herein, both singly and in
combination.
[00134] In certain embodiments, the present invention provides a compound of
formula I,
wherein n is 1, p is 1, q is 1, R2 is ¨CF3, R3 is hydrogen, R4 is hydrogen,
Ring A is piperidinyl,
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(R4)p
piperazinyl, or morpholinyl, and Ring B is \
Nssis, thereby forming a compound of
formula XIII-a, XIII-b, or XIII-c, respectively:
N N
(R1)m
(R1)m
N/7LN N N
cN
X /
XIII-a XIII-b
N
/y (R1)m
c0
XIII-c
or a pharmaceutically acceptable salt thereof, wherein each of le and m is as
defined above and
described in embodiments herein, both singly and in combination.
[00135] In certain embodiments, the present invention provides a compound of
formula I,
wherein n is 1, p is 1, q is 1, R2 is chloro, le is hydrogen, le is hydrogen,
Ring A is piperidinyl,
(R4)p
piperazinyl, or morpholinyl, and Ring B is \
Nssis, thereby forming a compound of
formula XIV-a, XIV-b, or XIV-c, respectively:
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N N
zi,L
N
z,l) N (R1)m
--- dR1)m ---- N
N N
....--Nµ
...1\...z1 cN
c........k X /
CI CI
XIV-a XIV-b
N
(R1)m
N*
NC
N N>
X1_ i
_1z1 0
CI
XIV-c
or a pharmaceutically acceptable salt thereof, wherein each of le and m is as
defined above and
described in embodiments herein, both singly and in combination.
[00136] In certain embodiments, the present invention provides a compound of
formula I,
wherein n is 1, p is 1, q is 1, R2 is ¨CHF2, le is hydrogen, le is hydrogen,
Ring A is piperidinyl,
(R4)p
N
jj
piperazinyl, or morpholinyl, and Ring B is V N
sss
ss' , thereby forming a compound of
formula XV-a, XV-b, or XV-c, respectively:
N
N NI
z,I,L
y (R1)m
--- N N ---- N N>
_1....\1......... N\z I\....I..... cN
F F
F F
XV-a XV-b
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Ni
/y m
---- N NR1)
N
\ 1\....1......, c0
X i
F
F
XV-c
or a pharmaceutically acceptable salt thereof, wherein each of le and m is as
defined above and
described in embodiments herein, both singly and in combination.
[00137] In certain embodiments, the present invention provides a compound of
formula I,
wherein n is 1, p is 1, q is 1, R2 is ¨CF3, R3 is hydrogen, le is hydrogen,
Ring A is piperidinyl,
(R4)p
N
1
'??2,Ni
piperazinyl, or morpholinyl, and Ring B is , thereby forming a compound of
formula XVI-a, XVI-b, or XVI-c, respectively:
/,17CN /1,CN
)( (R1)m
A (R1)m
N N N N
N N
.....N...... % cN
F F
F F
F F
XVI-a XVI-b
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)(
N/1,CN
(R1),,
N N>
% c0
\ i
F
F
F
XVI-c
or a pharmaceutically acceptable salt thereof, wherein each of R1 and m is as
defined above and
described in embodiments herein, both singly and in combination.
[00138] In certain embodiments, the present invention provides a compound of
formula I,
wherein n is 1, p is 1, q is 1, R2 is chloro, le is hydrogen, le is hydrogen,
Ring A is piperidinyl,
(R4)p
N
1
'??2,N.S
,
piperazinyl, or morpholinyl, and Ring B is , thereby forming a compound
of
formula XVII-a, XVII-b, or XVII-c, respectively:
j( )(
/,1,CN (R1)m /,1,CN
N N N N (R1)m
N..11.z1 N.I.......z\I cN
CI CI
XVII-a XVII-b
N/1,CN
j( (R1)m
N N>
..1.1.z1 c0
\ i
CI
XVII-c
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or a pharmaceutically acceptable salt thereof, wherein each of le and m is as
defined above and
described in embodiments herein, both singly and in combination.
[00139] In certain embodiments, the present invention provides a compound of
formula I,
wherein n is 1, p is 1, q is 1, R2 is ¨CHF2, le is hydrogen, le is hydrogen,
Ring A is piperidinyl,
(R4)p
N
piperazinyl, or morpholinyl, and Ring B is , thereby forming a compound of
formula XVIII-a, XVIII-b, or XVIII-c, respectively:
/,1,CN /1,CN
(R 1)m A (R1)m
N N N
cN
X /
XVIII-a XVIII-b
/1,CN
(R1)rn
N N
c0
XVIII-c
or a pharmaceutically acceptable salt thereof, wherein each of le and m is as
defined above and
described in embodiments herein, both singly and in combination.
[00140] In certain embodiments, the present invention provides a compound of
formula I,
wherein n is 1, p is 1, q is 1, R2 is cyclopropyl, le is hydrogen, le is
hydrogen, Ring A is
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(R4)p
piperidinyl, piperazinyl, or morpholinyl, and Ring B is , thereby forming
a
compound of formula XIX-a, XIX-b, or XIX-c, respectively:
N
(R 1)m N (R1)m
N N N
NC..c cN
XIX-a XIX-b
N (R1)m
N N
XIX-c
or a pharmaceutically acceptable salt thereof, wherein each of le and m is as
defined above and
described in embodiments herein, both singly and in combination.
[00141] In certain embodiments, the present invention provides a compound of
formula I,
wherein n is 1, p is 1, q is 1, R2 is azetidinyl, le is hydrogen, le is
hydrogen, Ring A is piperidinyl,
(R4)p
YeYpiperazinyl, or morpholinyl, and Ring B is , thereby forming a compound
of
formula XX-a, XX-b, or XX-c, respectively:
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)(
N"1" R16 NCN r......r N CN
( A (R1)m
N N --- N
....-N,
...11...z1 c.N
c........k \ /
No No
XX-a XX-b
N(
7.....CN
jL (R1)n.,
---- N N>
n c,0
No
xx_c
or a pharmaceutically acceptable salt thereof, wherein each of le and m is as
defined above and
described in embodiments herein, both singly and in combination.
[00142] In certain embodiments, the present invention provides a compound of
formula I,
F
N/-/--F
wherein n is 1, p is 1, q is 1, R s
2 i V , R3 is hydrogen, R4 is methyl, Ring
A is
(R4)p
N
1
\ Niss
piperidinyl, piperazinyl, or morpholinyl, and Ring B is , thereby forming
a
compound of formula XXI-a, XXI-b, or XXI-c, respectively:
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(R1)m (Ri)m
j( A
----- N N NP"----"N N
N
U n cN
q...... p......
F F
F
F
XXI-a XXI-b
j(
N/1,CN
N
(R1)n.,
---- N
U 0
\ /
Nq..._F
F
XXI-c
or a pharmaceutically acceptable salt thereof, wherein each of le and m is as
defined above and
described in embodiments herein, both singly and in combination.
[00143] Exemplary compounds of the invention are set forth in Table 1, below.
Table 1. Exemplary compounds of formula I
single stereoisomer single stereoisomer
0 ri
,S' r N NI c.N;
N HN \
1%1 H 1 yC,--.;
NN NN
.Y /N _o NN N
N
F F F F F F
I-1 1-2 1-3
62
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N ¨ sing
0 NH N" N"'"
N .---1:1 le stereoisomer single
stereoisomer
F
N 0..../ µ_N N F ----kN
NM N NM
\ / \ N \ N
F F 0 F 0
F F N N
F F H F H
1-4 1-5 1-6
single stereoisomer
\ ,0
S N ,C-r\i/
/s
N--)sN' 's, N ---'' , NH
N s) N'Ki HN -kNi-- '.---- .. -SZ .. N1-- N N
\ N _____________ )\_N .. r
\ N/
F F )--t F
F F
F F F F
1-7 1-8 1-9
single stereoisomer
N N
,;./,
/'-'-1- N N NI,---"Qi Ni Nr---(D\ ,
NH
N( 0 \ NTh \ N¨ N.---\r_CsN
\/ N
N
c,¨ \ NI
c,--0
F 0 F
F F F F F F
I-10 I-11 1-12
o
I,
N HN-S NI N NH
N\LI4*.N1) N\N N NNN
,N ,r0 N
F 0 \ N/
F F
F F F
1-13 1-14 1-15
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0n
N HNS''
NrrN y.."-N
NYNI N N\, N N-.-r-i\ N
q N, N N-:--.( CIH
\
F \ / 11:r
c...._0
F F F
F F F
1-16 1-17 1-18
N1--; 1\1%. N ---'
RP:A)0 ._,NEI
N/.----/%J\ HN1----\ N'- - - -4N \I _ _ _ _ cNI,NH N/r-
N, -k .. -
- U--1 ,-1-1\ N
\ N1/
c-0
\ NI/
\ /
CI CI CI
1-19 1-20 1-21
N N //-- r". \z.,,_4N1-')
N \
I )\
N---;/\ -N CNFI N
\ N 0' N r, - IN C) N N N-Nrc-N,NH
/ Th----CNH
-- 0
c-0
\ NI/
\-0
CI F CI F Br
1-22 1-23 1-24
Nr.--.
N -k N N
'/---4N
Nif--- N Nit.D.____CIFI
/N N '-.1
N --- N
n cNH
n
F Br
,-
CI CI
1-25 1-26 1-27
N%\ ,y(Njlp N %. . NHN
N N N N
N jr1
NN N N s
n, NH Cl..z
n / '0
i
\ /
CI Cl I CI
1-28 1-29 1-30
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single stereoisomer
single stereoisomer single stereoisomer
N *. N *.
r 1/ 'NH
,
a a
NN N N . -7'0 NNN NI' 7:0 N .,.. N
N
..11 / NH
\ / F
F F
F F F F F F
1-31 1-32 1-33
single stereoisomer
single stereoisomer single
stereoisomer
N ,-N
NH N jy -c-N N ,.1 -cir:/k
N/.."-/-= N N
N"-\--
...11 < NH
NH n NH
1.
\ 1 F \ Ni
\ /
F F Cl Cl
1-34 1-35 1-36
single stereoisomer
N ___N
N --N N -, -c-,N;
N
,C./11H
I lyZ/NH I NH "--- N N --..
--c-N N A.=---- .''s '''.
N N N N
% NH
% LNH
r....c LNH
F F F
F F F F F F
1-37 1-38 1-39
single diastereomer
single stereoisomer (pair of
enantiomers)
N*.1 N,
NH N NH
/===-1-= )N N _ rThs1 / ,
N N - ----"%i -1-( HN -'s Z
% NH
ttsl__ - N =-=== N N N
_.N..._z NH
\ /
F / F
F F F F F CI
1-40 1-41 1-42
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N N :/1,H N %\ .yc N:
I / N
jThµi
N I / N
-1) N N NP'-----rN N N
...N......c.,
NH 0
% 0
\ /
\ / \ /
F
F F
F F F F F F
1-43 1-44 1-45
single diastereomer single diastereomer
(pair of enantiomers) (pair of enantiomers)
N 0
N =-=% N '=--
HN HN
N '-'CN -I( s'S 'C) N r--N -1( S=0 N "-- N N NH2
N = t)N N =
\ /
CI Cl F Cl
1-46 1-47 1-48
single diastereomer single diastereomer
(pair of enantiomers) (pair of enantiomers)
N N ? N 1
N/1:zz=)N N N''S I j. u
/ = 0 NN NH2 N/'''-----N Ncr NH2
r ni ,
, ,
, ,
CI
F Cl Cl
1-49 1-50 1-51
single diastereomer single diastereomer
(pair of enantiomers) (pair of enantiomers)
N , ,u.L0 N , ,u.L0
I I
Nrµi NH2 N/'''--'-(LN N NH2
CI CI
F F
1-52 1-53
single diastereomer, pair of enantiomers racemic mixture single
diastereomer, pair of enantiomers
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i
1--.', r 0
-1,4>r N'". .,A 11/41
J I 0' N r )4¨j\N----....õ4. i4H
'!LEni
, õ , `.. - - .)- - Isi
f,=.=(.r..,N
..... f ......, \
%.,
F'
1-54 1-55 1-56
racemic mixture single enantiomer single enantiomer
N=-'= i . ' " :N. . .
N.-'1,;,-.7 it t.:4=:, m = -:,. ---4,: , 0 N''
'z!:----:-` ...k 9
N ''
.., i =,,,.....
4---i,1' \14'-'i411 ',.-i ' N - \,-..hf, ,5s---ii
,,).' \r=ow.
i .,. .:
vs .`, - - =
' \
i: 0 ;=:13 = r4:
1-57 1-58 1-59
single diastereomer, pair of enantiomers single
diastereomer, pair of enantiomers single enantiomer
FN GN FNN /
r\.............}¨\ NO
N
1-60 1-61 1-62
single enantiomer
ci
,./'..---...r-.......
.7... N ---0- ........,%............
0 N N
1-63 1-64 1-65
....---¨.....--.........._
CI
..,...-..,..,,,,..õ, CI
N
/ N
N
.....\./...) I /
0 N
1-66 1-67 1-68
,./..."\rõ..-......?_1 ...
EN F
/
\i,,......-N
)µ,..- 0
F N F N r...- iti-- NR
/ N N\....}......N
__)N\ j
67
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1-69 1-70 1-71
er.-___,.._N
1 /
CI .N / '
F / 0--,...?_N
_
CI
. CI F 0
Nvi___ 07,
N\...
N
1-72 1-73 1-74
,,r''=-= .. rõ.-N eTh.,-N
/"..------ij--,----NO)LNL
N
N
_.._.._ 0
µ,0 N,N
i 1 /
N\ x j... N
CI
F
1-75 1-76 1-77
CI N1 ..,..,,s,..õ,N-....?___ >..õ___
N N F F / N
O_ s--- NO__ N\___)___ /4
.Z.--- N N
1-78 1-79 1-80
_
161 CI F.õ._,....-...r.N
0
N
0 CI
N..,./_._ 0
/ N N N....,kv,N y. N
LN
...-N 0
1-81 1-82 1-83
N
N
/? N\
/ N
N CI
0
F
1-84 1-85 1-86
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single enantiomer single enantiomer
I\l')7NIII\ I,
/....,....1,11, ,
1\1/ NNH2
N N
0 N o
.\
Ntr1\1. NVIõe4
\ i
Cl Cl
II
F F CF3
1-87 1-88 1-89
single enantiomer single enantiomer single enantiomer
n N
0-N
1\l') 0-N
I\lr) N
a
N
N 0 N 0 N 0
n \ t..,,
\/ \i \i
CF3 CN CN
1-90 1-91 1-92
single diastereomer single diastereomer single
diastereomer
(pair of enantiomers) (pair of enantiomers) (pair of
enantiomers)
N) 04N Nir---- 0 0
4N
Nr:.----1- ..- 4N
0
--/¨_-_-(1---N N
Lo N (
0
Ntii)\1/ N ti..\14
CF3 CN Cl
1-93 1-94 1-95
N N N
I
N/Y
---... N N
N/)& N r\II I ----.\NH NNI\11
,N., NH (....N._zl .,N-,.e
H \\ Ny0
Cl Cl Cl
1-96 1-97 1-98
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N N NH N. NH
/õ...1A
N
/ANN
/
N N N ----- --.\
N N7'.1)."--- N N
CI CI CF3
1-99 I-100 I-101
F \ N-.......
F \ N--<
F / N
G
N II R F F
0 k./ N
--N d--- sS' ,`s NH
N
H 0 6 N
N\\ NH2
\F
c,0
1-102 1-103 1-104
N
FN FN \ --,..._ F \ N
N --_...._
F
F F / N F /\I
N / II
S>NN ..,...Nr.õ.(1\/1,NH N it 0µ N 11 0
\ \S-µS---N--"NriN 2\s----
c.,0 c0 11 b
0 H
1-105 1-106 1-107
FN FN \ --......_ F \ N,......._
F F F
F F ----N F ----N
S s_I
(:\ S. ,I 0
\\ ,
1\1:-LN N----r-CisNH \N1NMN
1-108 1-109 I-110
F \ N--...... F F \ N---,..._
Cl- 0,\,S
IL ,
_
(:\ N\ II
S--NNO/NN-S0--
0 H 0 H 0
I-111 1-112 1-113
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racemic mixture single diastereomer
N', I N I
racemic mixture \'-', \ 0....õ,
riCIYµ
N)
N F F F F
N \XN¨tcN
01-11
N'
N
N N413,0% im --- N N-L --- N
1¨F
F
:
-
CF3
1-114 1-115 1-116
single diastereomer
racemic mixture racemic
mixture
N N
* ..C:N H
N"=---"
N N'ssµ
N 'rNAN
C
\ NN NH 1\1,
0 N N,,, 1 uNH
.(Nr.jNIN1 N--N
N
CF3 F F CF3
1-117 1-118 1-119
single diastereomer
---NH
1 ......N ____tCNH
1
N N.soc_(µNH N N
N ¨N
NN
s_ co
i---)
)
0 N¨
\ z
F
F F Cl
1-120 1-122
N) NI
'NH
N /Ar\ N
j N I\14-
N7-.:.-1-- -N
/ '0 NI/Y*NN"µµ -7
...N.___ 0 ....N___ 0
F
F F F F F F
1-123 1-124 1-125
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/yrri N
'NH Z N
NH
N
'-- 1\1) N
N4/ .0, --.....z.f.
1\1 iiv N
Ni z()
NI/YNNyN, /
0'
F
\ /
F
F F
F
F C I
1-126 1-127 1-128
.-
_.,=_-N
r-\0 ----
Nr-Ni Nirµr-N N/ ,
F F ____--:.-N \----S--NH2 F F __.N 0 -N
\ F V
0
F N \ F N \ N e
)---z.--N )...--Nc
1-129 1-130 1-131
H
1\1
N
CIe\rIV......_ 1 Nr----17N Nv
0
CIN /
-N e N
-N ...___..c\\ N ei
NH F
FE
1-132 1-133 1-134
H H H
--N C N --N N
N /7 N
I 'N I 'N
11 GN
,,,µ =
N N N
iN Nv
N,---- N N
% 0
N%
\\ Ni Hr
\ i \ i
F F F
FE FE F E
1-135 1-136 1-137
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N ._----:-\- / /
NN NN
'NI
,--ci
/,1,CN I
'NI
N NI N N
% Lo
N N
F F F F
F F F F
1-138 1-139 1-140
/ / o-
_-N N
ri
;1 I 'NI
,sõi
/_;I I isN N N
.....õ N NO N....., N N N' (N N
N
:
F F F F
F F
F F
1-141 1-142 1-143
o-
rj o-
N , N
rj N
N r¨N JL ,CN
N' ---T N N
a
N' --T N N".''s ' ..N._.1 <
qF
F F F F
F F
1-144 1-145 1-146
Ni 0
I
N __N N
I 0
N
I 1\1/N
N.(1\1H2
NN,,,NL('NH
NI, 1\INNH2
1\1 \ N
.._< Hr0 (:_l_< \ /
\ / \ / F F
F F F
F F F F
1-147 1-148 1-149
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rN 0
N 0 Ni 0
I( N \/ N N- ,
NH2
NN N NH2 NNN'sµµ NH2 N
F F
F F F F
1-150 1-151 1-152
/
iNI:N
0 N 0
.,,,i N ---- N N
N N N lNH2 NNj-NANH2
\ N J -1
F F
F F F F
1-153 1-154 1-155
/
/ / N y N
7.,yrN N
N N N' N N N
zyr N r000c:\l, so
/N N ---- N N=
_..:.< L10 __NI.__< 0
\ / F
F F
F F
F F F F
1-156 1-157 1-158
0
N i-
OH
fyrN
N _. rµH
NN N'''%/ N "-- N N I / N NI, N N
Cz
0/ J
CI CI
1-159 1-160 1-161
74
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0
N j
NH \--- 2
N 0 N\ 0
N N N
.,,IL
, I N
N- NH2
__11z1 NLI\IN.NH2 N \ /
1 izi 0
CI \ / CI
CI
1-162 1-163 1-164
N
0 OH N 0NH2 N
I
Cz
NNN NN N,
N N#1\j4
N0-
1 0/
CI
F F F F
1-165 1-166 1-167
/yrN
/ya
N;NH
/yNN
N ."- N N
q -> -\
, I\IS/ N/ m
N N N \ N Hr NH
_IzI 0 / d
N
\ / F
\ / F F F
Cl F F
1-168 1-169 1-170
:(
N = _
/yr ;VC-I\I;N /ya -1\1\'
N 7ya NI
)ycµ
N N N H N N N H N, N N NH
_.NI < NH
_.NI < rNH .N.__.< NH c
F F F F F F
1-171 1-172 1-173
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N N
N 0 1
LNNNH NNN
N/ N 4. (-
IV,
NH
A
N N U NH2 .N.__.z 0 F N_z Hr0
F
\ / CI CI
CI
1-174 1-175 1-176
A
7yrN NH2
N NH2
N N N'N.C)
/yrN -N.clsNH
NNNIL
0 ..11_c 0
N N N
0 CI F F CI
1-177 1-178 1-179
/yrN __N ci N __N
/rN
A µN H a r..0,ciµN
cN
N N N'''' N N N H N H N
N=ss% -
_.N 0 NI__z Hi0
Cl CI CI
1-180 1-181 1-182
1\ N
,4-/1
/yrN NH2
N 1\1 N N N N0 A i\IH /yn --
'NH
N N N
.N.__.z
_ \ /
CI CI
CI
1-183 1-184 1-185
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N C 0.,,õ N N 1 N N
NH2
N N .'" N
N /IN /NINH
% µ
L.% \ / 0
CI F F F
F F
1-186 1-187 1-188
N:--.N rN 1\1=-"N
.*,,, Nl,,, ' HN
N N N N H N o N N=' N CI N p
NNN S/
/
N.__.z
F F F CI
1-189 1-190 1-191
N-
N NH2 ,NH._1, _
NNJ NrN F
NC)
F
----/-\J
\ /
NCr:L. \
F
F F N
1-192 1-193
yrN 0,4N/ /yr N N /yrN c/__NiNi F
,, N
N N N H N N N H N N N''"
(._11z1 : \
\ / -
(.__N__
CI CI CI
1-195 1-196 1-197
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ON H2
/yrN N /yrN ___N CNH CNH il
F
F...
CI CI F
1-198 1-199 1-200
OXN 0 N H2 /yr N rdo,
N.-- NF
i 1 i\I N N N 1 r-
!iN N y N 1/ / 1\1NyNF
o
F
I\1) N}
F F
F 7LF CI
F F
1-201 1-202 1-203
0 OH
C
N/y NI
rNN 0 OH
%I
JL ('NH 1
N ' 1 F
!NN . N F
F
\ / F N
N
F
CI F
F F
F
1-204 1-205 1-206
H2N ,c) 0
N /yCLN r---___N /yCLN _NI
r N)(0 )\1 JL ;1\1H .. JL NF
/ iN-KrNN) /\ N.I\i_ N N N
N z z
I Clµ
F \ / \ /
F
F CI Cl
1-207 1-208 1-209
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/yCLN -C1 0---
DI N
li NINH NH N
NN N'' N N N Cc\ N OH
F
CI CI F F
1-210 1-211 1-212
N 1 Ni <NC12 OH
NN N 0 N N NO
OH \ N OH
\ /
F ----c F
F F F F
1-213 1-214
(:).,N I-12
z,,,rril\I ...._N,
N
F N} rNH N NI\J
/
--jN 1 L
N)
..---/ /NI 1
\ /
CI 0 NH
F
1-217 1-218
ON H2
N
/yCL ......N
/ 1
tµNH j\( N
0-./,NH
/ N-
N"--NN/ N N N=s'
il \\ Ni 0 N N N
C_\ N
F FN 0
F
F CI CI
1-219 1-220 1-221
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0 N H2
-
/yCLN _....N
iF...õ\eõ:
II
s't N--
NH
N NN'' / illj\NrN 1/\I
N
\ / F F N j
F F..
CI F
F
F
1-222 1-223 1-224
F..F
\eF
n N
/ 1 CN
rC
:1\IDN 1 N
., /..N- N N
F F Fr
ZI\I-N N / y -
I
N N I\1)
F F F
F F F
1-225 1-226 1-227
0, N I-12
N N
NN;N '= \...
% N NE1 N N N
2 / ii\INN lr F %
I \ /
F F F H2 N
0
F
F F F F F
1-228 1-229 1-230
F
F F
CN
N-. N---
/ 1 (NH / 1 rTO 1;1 1
/ N.--MN N
NI--N N
N N1) N j
F FJ F
F F F
F F F
1-231 1-232 1-233
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/yrN ___N
C.10
N N NN gi
N/yriN _
C: IV
'NH
N .sõc;NH
/ iNIN N a
\c
F
N
=
F
F
1-234 1-235 1-236
N
-0\ro NI Ni
Nm
N NH
- ¨ I
NNN.µµ()F1 N-=/'.'1,----I.N---"-N----
',.,,,,NH2
\
_I\A OH OH OH
/z_
__N____
__N____
/ F \ / F
F \ / F
F F
F F F
1-237 1-238 1-239
Ni
NI
OH 1\1/ N N=
I 0
N
NNNF N NN
-)
__.[\___ NH2
OH \ / F
F
F
F F
F
F
1-240 1-241 1-242
N 0
N
1- N
NNNNH2
N\ N .sµr\IFI NN NN4') \ N N
_.N___z "OH \1/z
._1 / \ \ / F
I<FF
CI CI CI F F
1-243 1-244 1-245
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/yrN N NN _NI N
i( CNH /yN N ril _NI
N =s'µ N H N zyC II
\C;NH
NN ='µ
0 0
CI CI CI
1-246 1-247 1-248
\NH
NN N N __N
%
/yrN __N
N N N N /ya CNH N
iL
zµN11-1
N =s'µ
\ /
%
0
CI
1-249 1-250 1-251
N HOo N 0
y oyo NH 1 HO
NH
NN . N
NNN
NN No`INIFI
(:
1\1._c __1\1._c L.
_z
F
F OH \ /
-
OH
CI F F FE
1-252 1-253 1-254
HNar
14\ 1 0
N. N la
N/ N kN.õ N H2 I
/1\i/\ N ,0N1-12 1\1(N NNH
N
N..__z
Nli
OH
F
CI CI FE
1-255 1-256 1-257
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...00cN,
N / F
N N N 0 H 0
I N'ss NH2
/ya 0 _..lizi \
N
N N NNH2 \ / z- ....N..._.c
_..N..._.c N
\ /
\ /
y---7
L-1--F F
F F F F
F F
1-258 1-259 1-260
/yrN ,---___N
/1\1H
N N=s" Ni 0
N I
_..11.1
NI
I m 0 NN NYLNH2
N NI/LN N
_z F
L-1-"F
F \ / 1 \ F F
CN
1-261 1-262 1-263
/yNa 0
/yri 0 N _NI
N N H
1\1 N(NH2 N N ,"---
INIA NI-12 N N
\ (: NH
c c
-
F F CI
F F F F
1-264 1-265 1-266
N
Ni 1:z1H Ni NH
/=.,(Niki..,õN, p
N\ N iy ,s\
,
NNN NNN
_.N._.zL.NH
clZ
5,
P NO CI CI
CI CI
1-267 1-268 1-269
83
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
/yrN /1-N\
11 N /CINI N
N N N NH N NN H
'NH
N N N
Hr0 (12_1
=
CI No No
F
1-270 1-271 1-272
/yrN N
O /ya -Ni N
,\N NI
N N N H =s'µ - N N N H
0C;NI-1
=s
N N N
F CI F CI F ci
1-273 1-274 1-275
NF 0
lq 1\1/µ
NH /ya
c/1\1H NLI\I N NH2
1\1N N N N N
_.N__.z Ny \\ Ni F
0 0 F
CI CI F
1-276 1-277 1-278
o o0
(N _....N (N _....N N NI _
\ C;NH L NF
N/y N N N/y N N
L NH r ='µµ N/ya N N=sC;
1\1 µµ
\ / \ /
CI CI CI
1-279 1-280 1-281
84
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
N F 0õ0
0 µK 0
NiNN'ANH2
/yri N
N N
F;IC<
L.
N
\ / F
F CI CI
1-282 1-283 1-284
zyCL __N
>0 1 No.",cN H
7yNa N
0
I ../N 0 N 0
N N N I -
z
N1/NN H2
ri
\ /
F
CI
1-285 1-286 1-287
/(LN _NI
j( 'NH N
Ny N N I 0
.N.__ NNNN'4
\ / N / \
I NNNN149 F
(...1ZI
---7
N
z ,
1-1"--F 0-c-F
F / F
Br
1-288 1-289 1-290
X)
N
/yNa
N NN N NN
0
:CNN
N N=s'
NNNNIP .-\ N 0
\ / O_(F F 0*F
F F F
F o
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
1-291 1-292 1-293
Ni NI ji NH N N N
N
N N N I 0
\1H
N N N
/-. iNH
-
y----1
F F F
FE F E F E
1-294 1-295 1-296
HO 0 HO 0
ya ,s la N--1- 1
NN No; N/YNN N N N N./NH
CI CI CI
1-297 1-298 1-299
N, \e
/NNN4) 1\11 ycl/\ ,, NH
N Ni/N N
% / \ (..11µ
N
\ /
5, OH
CI
1-300 1-301 1-302
1
N RµIP N, N 0
,-
N H2N 0
r\l' NN NN N c:FIN N:N:NcrC)
\ / F F FF
CI F E
1-303 1-304 1-305
86
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
N
õ.1\/1,H
Ni 1 NI-NI
N N =
/)NN /
N, \ N
._..-.c OH
OH F
F F F
F F
1-307 1-308
N 0
N cl\l/sH
N N N
NH2
N -H2N...-0 7T,..,L
I i /NI s
N N N % N
NNJN
% NH \ /
\ / F F F
CI F F
1-309 1-310 1-311
N N NH /1H
N I
I sN
NIN.õN4:) /=,,NN N/\ '-'1)N N
N N
111 (.. s_
( 1\1 _._ I \ (N \ / OH
.S, ,S, F F
O'0 O'o
1-312 1-313 1-314
N NH N
I / N /yril
I 10
NNN 0 NLN N 'NSI
N
_
_.c
\ / .._z \ /
OH / F \ OH F Br
F F CI
1-315 1-316 1-317
87
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
N __N Ni __N
NaL/NH
NN Ni
/NaL/NF
---N NNN'''N14) N \ N
S"-NI
¶ H s.;-N H2
Ob \/ 6"0
-.N,.õc ,
00
1-318 1-319 1-320
Ni qIV .:\./1H Ni 0
I '
NNN / NI
q.,õõN/H /=,,r k
I /1\I N N NI 's% NH2
% NH
N/NN .N,
\ / % N
V
F F F F F
F F
1-321 1-322 1-323
,
N 0 N
I N NH / 2 NN /NNI40 N _N
N ___________________________________________________________________ J
\
_.:/ \ NAyNI NjcsNH
_..N..._z
F F Br
F
1-324 1-325 1-326
N Ni
NH
,,P N
NI
/LNI I NN'S n N/N I NaCN
H
\ / N/ NO ,o Nif-\
= F \ / o,
F F ,s-NH2
0'
0
1-327 1-328 1-329
88
CA 03089769 2020-07-27
WO 2019/148136
PCT/US2019/015473
N N O'N
,---
NNNN4) N
i \ NNN N
NNNr
.../4\ /
F F F
F F F
1-330 1-331 1-332
N
N N N' NN(
NN N NNN
% HN
_1.1
% NH \ /
\ /
7\
F F F F F F F
FE FE
1-333 1-334 1-335
N
N N H N 4
NNN NN NYL-'N N N µ/ N(....:_cN NONjI=()
"(As_ NO c NH \ /
F F F F
F F F F
1-336 1-337 1-338
Ni N O'N
NI NN NN N \.,,,N1453 NN N
/
N i \
\\ NI A"
00
F F F
F F F
1-339 1-340 1-341
89
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
N ___N
.k.,..( Ni .,4. .c-N
N N -
NI,
N N 'NH .,,oLcNI H
\\ NI/ y / NN N ---- NN N
o (._:c
F 'S. \ / \ /
F F F FF
F
F F
1-342 1-343 1-344
N
N,,,b
NI N
r___. Nb
N/r N Ncc l
"µ
'''' N/NNI\lcb NN N''''C'.(
\ /
%
\ /
F F F
F F F
F F
1-345 1-346 1-347
Ni ___N Ni
..,v'NH NI 0 I 0
N k
NN NYLNEI2
N N
NNN'ss NH2
F
V
CI
F F
CI
1-348 1-349 1-350
N ___N N
N N -c..;N H
N NN 'NH N- 1
,
N,
%NH (:. 1..._c N NN Ny -
CNI./NH
\ / \ / C___c N
F F HO
F F F N7
F F OH F F \\-0
1-351 1-352 1-353
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
N F
FSF Ni N--=-\
NNN 'NH
NI
% N I N- N N
/ iNN.õ.N
\ / NI/NNI / \ N
(__N___c
,.....---...., \ /
F
\ / F
F F o F FE
F F
1-354 1-355 1-356
NI 1 1
Nslill
N 1 /
NH
csc1,H Ni ycsNcIH /yL
I N
N N NNN kN 0
\\ N/ Hr N
F
F FF
F CI
F F F F
1-357 1-358 1-359
N--_ NH
N NH N 1 j....,C1sH
NI/NN4'N NNN's'N
(I) \ (_____ / Cla
F F
F
CI F F
FE F F
1-360 1-361 1-362
N - NH
N' JJIN -, N N N 1 ii-
N 1-1 s I sN
/
Cc , / N Ni/LN- -N
N N N o' L---/
(....11.1 \..._ N
\ /
\--a F
F F F FE
F F
1-363 1-364 1-365
91
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
NH
N - t\1H Ni t\1H
I zsN
N s'= N N''s e''1--)N Nj''s -
(....\..... N
% N N
F % F F F
F F F F
1-366 1-367 1-368
N NH
N/1,1-NI
Ni NH
N `- N N
/õ..., LN4 er:_ NCr'/N - N -
_._c\ N i,,N
,
N % N NZ\ /
N
F N
NH
\ /
F A F \./
F F
F F
FE 0
1-369 1-370 1-371
Ni NH Ni NH
Ni ,-N,I-1
NN N "
NI N NN N 4sNI
%
%
\ /
\ /
LN
\ / F eNNH F O
F
eNNH F F NI=.____ 0
F F N-(\F F
1-372 1-373 1-374
N 0-N Ni
___N
N
/j %µ -- .' N Ni
9 NNN FC'.-c
N (:)
NI/.'Y, NN '
\ i\___ic,
\ /
F
F
F F
F
1-375 1-376 1-377
92
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
0 NH2
N
N,
i I YNH Nr)
N NN N
_/....N.--NN.)
(_.N_____ NH
- :,../ND\rNN.7.\
I \ /
N
F Nj
F 0 NH2
F F
F
F F F
1-378 1-379 1-380
01
N
NI,-1 N-NH
N OH
%\II N
NNyN
ciNI-N, Nj
N N
F
FI
F
F F '
1-382 1-383
0
N-NH N-NH
V V A N
H 0
N N
/ 1 (--N-vN
/_,erN) Nk' / _____/N-Nr
N N N
F F
F F F F F
F F
1-384 1-385 1-386
93
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
0 0
0- 04
----A N ---jc N
0., NH2
N
rNI`
4N
p\I-3N,L--)
F
ciN-KeN---)
NI N
FI -3NTN
N
CI
F F F F
1-387 1-388 1-389
õi
N-NH ?
N-NH
d---N1/1
N N 0 \I
5N-KrN, Nj N N N N
I j) ,\\Ncl --
NI
F
/ /1V-
N
Nlj FN 1
F F F '
F
F'
1-390 1-391 1-392
NC 0\ 0
---N1)
N
N N N
N
/ /1\131\jr N N
1\1--ir NYN-) 1
I N HN
.0
S' -----cF
F
F / F
F F F
1-393 1-394 1-395
0\ 0
N-NH NI ___N\
/ANN N \ a I
0/1\1F
N, o NIN N
N r-N)v c_\ N
, 'N----krN,-N-)
' N-
F
F
F F
1-396 1-397 1-398
94
CA 03089769 2020-07-27
WO 2019/148136
PCT/US2019/015473
N-NH
NI ___N
0
/NN.,,,c/\NIH N
N N--)r r-N k
z .,N,,,....N....,$))1 NNNM.".
\ / 1 F F
0 .
F -- NI.7
F FF 1 0
F;
1-399 1-400 1-401
N¨NH
Li... 0
N N
N - -
N--1 NF k NI/A
N N µµ
%
F N ''''= N Ni".
/ iniN NJ % N \ N 6
HO
I ...ic
----- N 0 F
FE F F F F
FE
1-402 1-403 1-404
N
N E 0
N,
µ=
N-S
µµ
NN N YC'Sµµ e---'re NI-V
;2, b
N
0 H
\ N 0 H \ N Ni8
\ /
%
F \ /
F ...._/._
F FF
FE F F
1-405 1-406 1-407
F
N N-
RH F F
N N-NH
I N
N/)NN NN=s`kc\NI ?"-N/ 11 < NN il \
il\I-NNJ--."* NI
=
F F
E F E F F F F
1-408 1-409 1-410
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
0 Y---
1-0
N HoN
Hi\I lz
0
1;1 1 i NNNJ /
NrNjNj
ir\i-Dy,õ.N
1
NI
N
Nj
F F F F F F F F F
1-411 1-412 1-413
H H
0 N-N NJ' N
ril 1 N N
,\\N
Nri\INJ ,A N
N / /N---ke N
N
/ iNI-Ny"
' N
1
N N
F r F HO F
F ' F F F F -J
1-414 1-415 1-416
H H
N-N N-N
0
0 N-NH
0
N N __
\j
1\ ,"N N
ciN-rN NJ) N
NN
, iN N
.3N) -
NJ ,
NI zN
N
0
F F F
F F F F F F
1-417 1-418 1-419
96
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
N-NH
0 N-NH N-NH
U00
N Nj..¨OH
5N--3"/NI") N NiC¨OH N r----N)-.
N,1
1 1
El\1
N
F
F , N F
F ' N
FF F F
1-420 1-421 1-422
N-NH
0
NH2
0NH2
NA A
;"" 1
1 N-N __
N) \IN-1,r.N
N
'IL) F _- I
F N. N
F F CI ci
1-423 1-424 1-425
N-NH
0 NH
2
Ni
NcµNH
N N Ii\I 1 Y.NH
N ro
N
Y F / 1\1-N/1\1-3rN r N
F , N
\ / F Yi--- N.
CI
F
1-426 1-427 1-428
rNH
Ii
\I
_.../),.õ.r.õ,NNINN,
F , I
N
1-429
97
CA 03089769 2020-07-27
WO 2019/148136
PCT/US2019/015473
NC\J
N-NH
X
0 NI
N rN)A I
.../N N NH NN.) CN NLI\I N
/ /1\13N N _____cN 1):NH
N1 j
NI
F
F
F F F 0
NH2
F
F F F
1-432 1-433 1-434
I
NI N ,S=0
HN %% r
/A 0
N' 'NN F
i\i/YNN
=N N N N
\ N õ,=H
\ /
%
F 0 NH2
1\1._c cf\IH
\ /
F
F FF 0
F F F F
1-435 1-436 1-437
N N N.
I\1N N I'''µ.
HrNy,t )\F N N NI
\ NN /LNN NN
IrNiy
N,
0
11'0 0
0 F
F F F F F
F F
1-438 1-439 1-440
N-NH N-NH
N-NH
0 0
0
N NN N
/N-3N 1 NN-,6 i /N--N 1 N c
N, ..-
,.., N
N. F F
F ' F F
F
F '
1-441 1-442 1-443
98
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
N-NH
N-NH N-NH
0
0
0
il N).____I
N N)._ N1
N N--
.) µ.------N
/ N-Le , N----) \N-0 / /N---Kr,NN---) NH
I I N
N N F
F '
F F F F F F
1-444 1-445 1-446
N-NH F
0õ;) 0õp
N _N 'N
N N N N N
/ .__ /Aill N r-N-
___ Nj
---- N
---------\ F F F
F F
F F F F
1-447 1-448 1-449
F
F
N-NH 40
N-NH
0
dN r-N
_ /...1\1-3rNI, N-) N
i
1\1.7 N NH
N1--3NNI-)
Ni.j
ON-3121;rNrNH2
F I F
F F --- N 0 F ,
CI
1-450 1-451 1-452
0*.võNH2 OrNH2
N yNH
/ NNNJI
F / /1\I-N 1 r\l)
F y
I
I\1) N
1-454 1-455
99
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
F
F
N¨NH th
N¨NH N¨NH
H.
0
\I
N N N 1/ 1 N
_ i__,N-3(Ni Nj
N1 _ /_./IN-N N J 1
N.
Nj F
F F F F
F F F F
1-456 1-457 1-458
N¨NH 40 N-
N¨NH / 9
--N
F N¨NH F
/ F
N N
1/1
N %\i
_ /.../11-Ni\j N
N --) N NJ
I
!..../N;
_/N-3r N N -.) 1\1)
F N F
F F
F F F
F F
1-459 1-460 1-461
NI
N' 1
N
rL N/)NN'ssNµ
N To
/N--3C1 N ..,,N...4
F
F F F -
F F F F (D,
1-462 1-463 1-464
il
N _
-
r.
/ N NrNn.õL / N N-Tr-N õ
. __.
IN , N / N \ N i /N
N N.õ....,..--..õN.õ.
N )-----N' N )-----14 11
}:"----NIN
F F F
F F F F F F
1-465 1-466 1-467
100
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
H
N--"N
1._ N N
0
NhcP -H N __N
e z) N NN
0
yc/sNH
N
cyl--N, N--) N % N
1 rN N
N
NI 0 F 1<F
F F F
F F F F
F
F
1-468 1-469 1-470
I
N ,s=0
HN %% _NI
0 N 1
N y.c.;NNN'''µI N R N N H
\
' 1\(:_c_ NH NI/NNii N'µS( s N N
N
A\
F F F FE
F
1-471 1-472 1-473
Ni ___N NI _NI
N-NH
H 'NH
N N- -N1 /
0 H 0 NI, N N H
(...__N_c N4 _...1\1\_ N
N (---N,
\ / \ i
F F F F
100
FF F
1-474 1-475 1-476
0
N, N N-
'1'
y
0=s
/'NH 1
NiANNNH NN N
N re
_IV_c N
N õ N-
F
L<F FF
F \ /
F FF - 0
FE F F
1-477 1-478 1-479
101
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
,Ns NH
1)
N 14_71H
¨,_ N
ON/---1) i\lN N N N
NN
X
N _I\ N ry
tk
sU
F 0
0 F 0 F
F F
F
F F F
1-480 1-481 1-482
H
N---"N
.., 0
0
1\1)\''''c
c
N h)LCIN N NN NJ
ON I
rNy\ , /N3,N,-, NJ '
NI
' N N--3
F NrNH2
F F --- N I 0 F
F '
CI
1-483 1-484 1-485
N-NH
Ni N-NH LL
N N F
NNN'ssµµ 0
% N N r-Ni) cNI3y,N,)
N1
N
F F FF F
F
F F F
1-486 1-487 1-488
0
H µ`s/
NN N = HN--`
N /LI\IN s
NJ N =s
N)\"..c. NH
N NN N4-1\I; N\..__
N
i /N-3NY N.N_c
--
F I
1\17 \ /
F P
,s,
6 \ /
F FF -
F ' F F
102
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
1-489 1-490 1-491
(:)µµ
N -S
N -S\
/Y*1\ljN('-y1Cr 1 HN \ /Ae.NN
N \ `'
N N/Le-N"sµin N
F
F F F FE
FE
1-492 1-493 1-494
N _...N --=--
N
,
/Ae... I \c/\NH rFtE N o
N " s
_..N.s.._ N N/VNNN,s- N,
"\(A___, c,NH H b I 1 N ro
F /;- \ / / 1\l' yl\k).=,,,
0
F F F N)
F
F F
1-495 1-496 1-497
-=---N 0
NNO N -\\S
1 1 1-
7 b
I N
N N / N/\ Y" irY
, 1 0 N N N `. C / c. d N
._5NN y N \ N V
NO F
F (------F F E
F F
1-498 1-499 1-500
)1:1 N
1
CNH
N
N ---- 1\1 N"ssµ
\ N N
o N
\ /
%
F NI\ I, NN/\NH N, 1\1N=sµ
\ N
\ i
% N
\ /
F V
F F F CI:00
F F
F F
103
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
1-501 1-502 1-503
R
N
__N C, N
N
I
7.,,..,1)NkNNH , HN xµ
/L1 - - 0 N
1\1
(NNY:
:_Zx_ N N NN 1\1
,
\ /
V F
F F F F F
F F
1-504 1-505 1-506
R\
I\1 = HN-S N-NH
INI 4-NI;NH
o
/*AN \\ /NN
N N . N,
Nfi---0c0H
%
\ /
NI-3rNIN)
I
F F N
F F F F F F F
1-507 1-508 1-509
1\1,
1\11 4,./.._ NH
N. _NI
/yINkN .'oc;NH
,/--IAI N N
N
N rl\I y I 'NH 1\1µ
N/YNN _____cµ
N
FF F F F
F F
1-510 1-511 1-512
N-NH N-NH
I
N 0 /--\
0
NNN NO /( )----Y N
N)L-CP
¨N
I/1 \ ) OH / /N-.3rNiN___)
\ i 0
NI--NN/ N
NI
F
F
F F F F
F
F r
104
CA 03089769 2020-07-27
WO 2019/148136 PCT/US2019/015473
1-513 1-514 1-515
N-NH
N
0
=)\--f-N
N N N 1
(:)µµ N
N-0
\ N N µb NN N'Tho'vN-Sµr / /N-N NJ
(..\ ./...
F \ Nq.._ cNN\7,F1
\ /
,. ..--
I
N
F F F F '
F
1-516 1-517 1-518
/yr\rl r\/1\1\1H /yNa
N-NH ,/sN1H
0 N N N N, N N."
(f_c N
N N)LrN %N Cr\i,00
6 \ /
-
c/N-N N J F F
I
N. F F F F
L\00
F F F
1-519 1-520 1-521
N /yrl 4- /-1\iµNH
i r-_N\ N -.., N N
N
N1H \ N crI
N N
/yNa
NOH
N
------\F cN \ /
F FF -:
- \ 1\(_. 1._c 0
LOO \ F
F F
'00 F
1-522 1-523 1-524
(:)N 1
\\
/ya f,4-j:N;NH _ Na 00 -OH
/yrNI C N N
No l
!NH N N N /YLN '
N N N N4 \Nõ N
F
\ / q----\ F F
L\----
F F F F F F F
F
F
1-525 1-526 1-527
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N N
\
N
\c/NH /yla 4/NH I 0
1\1 N N N \ \\
/.N 'sµ N ,S
NNNN
\\
qc_ cl\I4 N
\ c1\1
\ / \ /
b
F F
AV- F 0
F F F F F
1-528 1-529 1-530
N-NH N-NH
0
\\
N 0-=S
N /YLI NH rNH
NNIIH 1/ 1 1/ 1
_..1\1___c
NNI\1) NNI\1)
\ i ' F 1\1) ' N-
F
F /F
F
F p F p
F ' F '
1-531 1-532 1-533
N-NH N-NH N-NH
i
..... LL1 ti,.õ1
\ I .. 1 NH
%\i 1 ia....CNI-1
%\i
NN N j i Nri\iNj i
Nri\yNj
' 1\1> ' N-
N
F F F
F F F F F F
1-534 1-535 1-536
N-NH
Q N _-N N
c__Ncµ
NH r\i/.N.so õ, NH
1/ 1 /,,,.CNH el, NN..4(
/ NNNj
\ /
' N.
CI CI
F F
F p
F '
1-537 1-538 1-539
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N
CNI(µNH /yCll 0µµ /7C1
-CNN
NNN''µµ
N ''= N N
\\ N Sµ
N µ0 N N N'ssµ
\N 1\k
\ /
<F CI F
F
Th
F F F F 0
1-540 1-541 1-542
s/-1\1, N 4--N;
N --=-= N N's N µ),
N/".:=-.."- -N N NH
/---=-=,-N N NH
LN
F F
....___..cN N.N._.1 c_
\ / F
\ i
F F
F F 0
F F 0
1-543 1-544 1-545
N N
r___
\
..õL:.....:/NH
NN N '
N
\ /
N
r NA N
rNA
%
F
Oki-N NrNH2 ONIN N.).õ NH2
F F 0
N N =
I
0 i ir
0
CI CI
1-546 1-547 1-548
H
N, \-N
H
C?\ 1 N-N N-NH
0)\_ e z)
(---. N17--'
¨Ni 0
Nii \ N V p
N---1 ¨NI N r-
Ny\,
Ni--3,,NyNI)
Ni-kC Nk) CN
' N NJ
I r
F
F F
N N
F F F
F ' F
1-549 1-550 1-551
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N 4....N/
NH r--___N NI r¨_Ns
N
NNN Ni/yNN .ss,,./:NH 0A,,/NH
% N2\\7 1- N N Nn
NJI
_
F
AV
F F q----\ F
AV ¨As¨\ F
F F F F
1-552 1-553 1-554
Ni N
N 4._/,
NH
N -N
NYNN _ , ocNH 7...,IANN,õ_.,.;NH
Nj/------r -N Nn"
N
% N
_
F
AV F :3C-\--(3
F
o 8
F F F F F F
1-555 1-556 1-557
NI NH
I
rNN41\1
N 0 N NH
0
NNN)LNH2 NN N
/9's%µ//µN \\ N/
F
F F
CI
F CI
1-558 1-559 1-560
N 0 NI 1 r¨ NH
N N,I-1 I
/N
N NYINH2 N NN
\
N/\ YL''
rNH
\ / F CI
CI F F
1-561 1-562 1-563
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N NH N ¨ NH
N GN N'- 1¨ 0--1\1,N1
NNN=s%µ / NI' N -1\l'sµµ
NrLI\IN's%'C'
cl\k,..___I 0
F --------F CI
F F F F
1-564 1-565 1-566
N ,
N NH I
1\1 N =sµ NI s/. Ni i 1\1 NI/-Y
NNN''
N N N µ1\1 \ N
\\ Ni \ yNH \ /
\ NI
F
F F
CI
F F F
1-567 1-568 1-569
V
Nl 0
/ NNN
' N 0
F
F F
1-570
[00144] In some embodiments, the present invention provides a compound set
forth in Table
1, above, or a pharmaceutically acceptable salt thereof.
[00145] In certain embodiments, the present invention provides a complex
comprising GCN2
and an inhibitor.
4. General Methods of
Providing the Present Compounds
[00146] The compounds of this invention may be prepared or isolated in general
by synthetic
and/or semi-synthetic methods known to those skilled in the art for analogous
compounds and by
methods described in detail in the Examples, herein.
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[00147] In the Schemes below, where a particular protecting group ("PG"),
leaving group
("LG"), or transformation condition is depicted, one of ordinary skill in the
art will appreciate that
other protecting groups, leaving groups, and transformation conditions are
also suitable and are
contemplated. Such groups and transformations are described in detail in
March's Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J.
March, 5th Edition,
John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock,
2' Edition,
John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W.
Greene and P. G.
M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of each of which
is hereby incorporated
herein by reference.
[00148] As used herein, the phrase "leaving group" (LG) includes, but is not
limited to,
halogens (e.g. fluoride, chloride, bromide, iodide), sulfonates (e.g.
mesylate, tosylate,
benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.
[00149] As used herein, the phrase "oxygen protecting group" includes, for
example, carbonyl
protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups
are well known
in the art and include those described in detail in Protecting Groups in
Organic Synthesis, T. W.
Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety
of which is
incorporated herein by reference. Examples of suitable hydroxyl protecting
groups include, but
are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers,
arylalkyl ethers, and
alkoxyalkyl ethers. Examples of such esters include formates, acetates,
carbonates, and sulfonates.
Specific examples include formate, benzoyl formate, chloroacetate,
trifluoroacetate,
methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-
phenylpropionate, 4-
oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl),
crotonate, 4-methoxy-
crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such
as methyl, 9-
fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-
(phenylsulfonyl)ethyl,
vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include
trimethylsilyl, triethylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other
trialkyl silyl ethers. Alkyl
ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-
butyl, allyl, and
allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals
such as methoxymethyl,
m ethylthi om ethyl, (2-methoxyethoxy)methyl, b enzyl oxym ethyl,
b eta-
(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of
arylalkyl ethers include
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benzyl, p-methoxyb enzyl (MPM), 3 ,4-dim ethoxyb enzyl, 0-nitrobenzyl, p-
nitrobenzyl,
p-halobenzyl, 2,6-di chl orob enzyl, p-cyanobenzyl, and 2- and 4-pi colyl .
[00150] Amino protecting groups are well known in the art and include those
described in detail
in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd
edition, John
Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
Suitable amino
protecting groups include, but are not limited to, aralkylamines, carbamates,
cyclic imides, allyl
amines, amides, and the like. Examples of such groups include t-
butyloxycarbonyl (BOC),
ethyl oxyc arb onyl, methyl oxycarbonyl, trichloroethyloxycarbonyl,
allyloxycarbonyl (Alloc),
benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn),
fluorenylmethylcarbonyl (Fmoc),
formyl, acetyl, chloroacetyl, di chl oroacetyl, trichloroacetyl, phenyl
acetyl, trifluoroacetyl, b enzoyl,
and the like.
[00151] Scheme 1: General scheme for the preparation of compounds of formula I
where Ring
B is a pyrimidine linked to the bicyclic core from position 2, le is hydrogen,
R4 is hydrogen, p is
1, and q is 1.
N N N N
H2N I I
¨N ( cyclisation N NSMe chlorination
t N ) ________ ..- NNCI sNA, NN---
A
I \ b tN l
\ 1 ?
(R)n 1 1
(R2)n (R2)n (R2)n
I-il 1-i2 1-i3 1
[00152] In Scheme 1 above, each of Ring A, le, R2, m and n is as defined above
and below and
in classes and subclasses as described herein.
[00153] Scheme 2: General scheme for the preparation of compounds of formula I
where Ring
B is a pyrimidine linked to the bicyclic core from position 2, le is hydrogen,
R4 is hydrogen, n is
1, p is 1, and q is 1.
N N N \
I
N,NyN x Pd-assisted pl r-NIA, N OR activafion Nrõ....-
1
N N OH
N/J cross-cou i ... ng N)_\ ' deprotection )_\/,\rLN then SNAr
0
R1 6
R2 R2 R2 R2
1-14 1-i5 1-i6 1
I
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[00154] In Scheme 2 above, each of Ring A, le, R2, and m is as defined above
and below and
in classes and subclasses as described herein.
[00155] Scheme 3: General scheme for the preparation of compounds of formula I
where Ring
B is a pyrimidine linked to the bicyclic core from position 2, le is hydrogen,
R4 is hydrogen, p is
1, and q is 1.
H2N N \
_N cyclisation NNCI SNAr NN
(i)
(1)1 A
(R1),
(R2)n
(R2)n (R2)n
1-il 1-i7 1
[00156] In Scheme 3 above, each of Ring A, le, R2, m and n is as defined above
and below and
in classes and subclasses as described herein.
[00157] Scheme 4: General scheme for the preparation of compounds of formula I
where Ring
B is a pyrimidine linked to the bicyclic core from position 4, le is hydrogen,
R4 is hydrogen, n is
1, p is 1, and q is 1.
NX I
y_rN
Pd-assisted NI\r CI N X
cross-coupling
SNAr
?_N
A
(R1),
R2 R2 R2
1-14 1-18 1
[00158] In Scheme 4 above, each of Ring A, le, R2, and m is as defined above
and below and
in classes and subclasses as described herein.
[00159] One of skill in the art will appreciate that a compound of formula I
may contain one or
more stereocenters, and may be present as an racemic or diastereomeric
mixture. One of skill in
the art will also appreciate that there are many methods known in the art for
the separation of
isomers to obtain stereoenriched or stereopure isomers of those compounds,
including but not
limited to HPLC, chiral HPLC, fractional crystallization of diastereomeric
salts, kinetic enzymatic
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resolution (e.g. by fungal-, bacterial-, or animal-derived lipases or
esterases), and formation of
covalent diastereomeric derivatives using an enantioenriched reagent.
[00160] One of skill in the art will appreciate that various functional
groups present in
compounds of the invention such as aliphatic groups, alcohols, carboxylic
acids, esters, amides,
aldehydes, halogens and nitriles can be interconverted by techniques well
known in the art
including, but not limited to reduction, oxidation, esterification,
hydrolysis, partial oxidation,
partial reduction, halogenation, dehydration, partial hydration, and
hydration. "March's Advanced
Organic Chemistry", 5th E
a Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York:
2001, the entirety of which is incorporated herein by reference. Such
interconversions may require
one or more of the aforementioned techniques, and certain methods for
synthesizing compounds
of the invention are described below in the Exemplification.
5. Uses, Formulation and Administration
a. Pharmaceutically acceptable compositions
[00161] According to another embodiment, the invention provides a composition
comprising a
compound of this invention or a pharmaceutically acceptable derivative thereof
and a
pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of
compound in
compositions of this invention is such that is effective to measurably inhibit
GCN2 protein kinase,
or a mutant thereof, in a biological sample or in a patient. In certain
embodiments, the amount of
compound in compositions of this invention is such that is effective to
measurably inhibit GCN2
protein kinase, or a mutant thereof, in a biological sample or in a patient.
In certain embodiments,
a composition of this invention is formulated for administration to a patient
in need of such
composition. In some embodiments, a composition of this invention is
formulated for oral
administration to a patient.
[00162] The term "patient," as used herein, means an animal, preferably a
mammal, and most
preferably a human.
[00163] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle"
refers to a non-
toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological
activity of the
compound with which it is formulated. Pharmaceutically acceptable carriers,
adjuvants or vehicles
that may be used in the compositions of this invention include, but are not
limited to, ion
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exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as
human serum albumin,
buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate,
partial glyceride
mixtures of saturated vegetable fatty acids, water, salts or electrolytes,
such as protamine sulfate,
disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride,
zinc salts,
colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-
based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes,
polyethylene-
polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[00164] A "pharmaceutically acceptable derivative" means any non-toxic salt,
ester, salt of an
ester or other derivative of a compound of this invention that, upon
administration to a recipient,
is capable of providing, either directly or indirectly, a compound of this
invention or an inhibitorily
active metabolite or residue thereof
[00165] As used herein, the term "inhibitorily active metabolite or residue
thereof' means that
a metabolite or residue thereof is also an inhibitor of GCN2 protein kinase,
or a mutant thereof
[00166] Compositions of the present invention may be administered orally,
parenterally, by
inhalation spray, topically, rectally, nasally, buccally, vaginally or via an
implanted reservoir. The
term "parenteral" as used herein includes subcutaneous, intravenous,
intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and
intracranial injection or
infusion techniques. Preferably, the compositions are administered orally,
intraperitoneally or
intravenously. Sterile injectable forms of the compositions of this invention
may be aqueous or
oleaginous suspension. These suspensions may be formulated according to
techniques known in
the art using suitable dispersing or wetting agents and suspending agents. The
sterile injectable
preparation may also be a sterile injectable solution or suspension in a non-
toxic parenterally
acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
Among the acceptable
vehicles and solvents that may be employed are water, Ringer's solution and
isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or
suspending medium.
[00167] For this purpose, any bland fixed oil may be employed including
synthetic mono- or
di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives
are useful in the
preparation of injectables, as are natural pharmaceutically-acceptable oils,
such as olive oil or
castor oil, especially in their polyoxyethylated versions. These oil solutions
or suspensions may
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also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl
cellulose or similar
dispersing agents that are commonly used in the formulation of
pharmaceutically acceptable
dosage forms including emulsions and suspensions. Other commonly used
surfactants, such as
Tweens, Spans and other emulsifying agents or bioavailability enhancers which
are commonly
used in the manufacture of pharmaceutically acceptable solid, liquid, or other
dosage forms may
also be used for the purposes of formulation.
[00168] Pharmaceutically acceptable compositions of this invention may be
orally administered
in any orally acceptable dosage form including, but not limited to, capsules,
tablets, aqueous
suspensions or solutions. In the case of tablets for oral use, carriers
commonly used include lactose
and corn starch. Lubricating agents, such as magnesium stearate, are also
typically added. For
oral administration in a capsule form, useful diluents include lactose and
dried cornstarch. When
aqueous suspensions are required for oral use, the active ingredient is
combined with emulsifying
and suspending agents. If desired, certain sweetening, flavoring or coloring
agents may also be
added.
[00169] Alternatively, pharmaceutically acceptable compositions of this
invention may be
administered in the form of suppositories for rectal administration. These can
be prepared by
mixing the agent with a suitable non-irritating excipient that is solid at
room temperature but liquid
at rectal temperature and therefore will melt in the rectum to release the
drug. Such materials
include cocoa butter, beeswax and polyethylene glycols.
[00170] Pharmaceutically acceptable compositions of this invention may also be
administered
topically, especially when the target of treatment includes areas or organs
readily accessible by
topical application, including diseases of the eye, the skin, or the lower
intestinal tract. Suitable
topical formulations are readily prepared for each of these areas or organs.
[00171] Topical application for the lower intestinal tract can be effected
in a rectal suppository
formulation (see above) or in a suitable enema formulation. Topically-
transdermal patches may
also be used.
[00172] For topical applications, provided pharmaceutically acceptable
compositions may be
formulated in a suitable ointment containing the active component suspended or
dissolved in one
or more carriers. Carriers for topical administration of compounds of this
invention include, but
are not limited to, mineral oil, liquid petrolatum, white petrolatum,
propylene glycol,
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polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
Alternatively,
provided pharmaceutically acceptable compositions can be formulated in a
suitable lotion or cream
containing the active components suspended or dissolved in one or more
pharmaceutically
acceptable carriers. Suitable carriers include, but are not limited to,
mineral oil, sorbitan
monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-
octyldodecanol, benzyl alcohol
and water.
[00173] For ophthalmic use, provided pharmaceutically acceptable compositions
may be
formulated as micronized suspensions in isotonic, pH adjusted sterile saline,
or, preferably, as
solutions in isotonic, pH adjusted sterile saline, either with or without a
preservative such as
benzylalkonium chloride. Alternatively, for ophthalmic uses, the
pharmaceutically acceptable
compositions may be formulated in an ointment such as petrolatum.
[00174] Pharmaceutically acceptable compositions of this invention may also be
administered
by nasal aerosol or inhalation. Such compositions are prepared according to
techniques well-
known in the art of pharmaceutical formulation and may be prepared as
solutions in saline,
employing benzyl alcohol or other suitable preservatives, absorption promoters
to enhance
bioavailability, fluorocarbons, and/or other conventional solubilizing or
dispersing agents.
[00175] Most preferably, pharmaceutically acceptable compositions of this
invention are
formulated for oral administration. Such formulations may be administered with
or without food.
In some embodiments, pharmaceutically acceptable compositions of this
invention are
administered without food. In other embodiments, pharmaceutically acceptable
compositions of
this invention are administered with food.
[00176] The amount of compounds of the present invention that may be combined
with the
carrier materials to produce a composition in a single dosage form will vary
depending upon the
host treated, the particular mode of administration. Preferably, provided
compositions should be
formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the
inhibitor can be
administered to a patient receiving these compositions.
[00177] It should also be understood that a specific dosage and treatment
regimen for any
particular patient will depend upon a variety of factors, including the
activity of the specific
compound employed, the age, body weight, general health, sex, diet, time of
administration, rate
of excretion, drug combination, and the judgment of the treating physician and
the severity of the
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particular disease being treated. The amount of a compound of the present
invention in the
composition will also depend upon the particular compound in the composition.
b. Uses of Compounds and Pharmaceutically Acceptable
Compositions
[00178] Compounds and compositions described herein are generally useful for
the inhibition
of GCN2 kinase activity.
[00179] The activity of a compound utilized in this invention as an inhibitor
of GCN2, or a
mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro
assays include assays that
determine inhibition of either the phosphorylation activity and/or the
subsequent functional
consequences, or ATPase activity of activated GCN2, or a mutant thereof
Alternate in vitro assays
quantitate the ability of the inhibitor to bind to GCN2. Inhibitor binding may
be measured by
radiolabeling the inhibitor prior to binding, isolating the inhibitor/GCN2
complex and determining
the amount of radiolabel bound. Alternatively, inhibitor binding may be
determined by running a
competition experiment where new inhibitors are incubated with GCN2 bound to
known
radioligands. Detailed conditions for assaying a compound utilized in this
invention as an inhibitor
of GCN2, or a mutant thereof, are set forth in the Examples below.
[00180] As used herein, the terms "treatment," "treat," and "treating"
refer to reversing,
alleviating, delaying the onset of, or inhibiting the progress of a disease or
disorder, or one or more
symptoms thereof, as described herein. In some embodiments, treatment may be
administered
after one or more symptoms have developed. In other embodiments, treatment may
be
administered in the absence of symptoms. For example, treatment may be
administered to a
susceptible individual prior to the onset of symptoms (e.g., in light of a
history of symptoms and/or
in light of genetic or other susceptibility factors). Treatment may also be
continued after symptoms
have resolved, for example to prevent or delay their recurrence.
[00181] Provided compounds are inhibitors of one of more of GCN2 and are
therefore useful
for treating one or more disorders associated with activity of GCN2. Thus, in
certain embodiments,
the present invention provides a method for treating a GCN2-mediated disorder
comprising the
step of administering to a patient in need thereof a compound of the present
invention, or
pharmaceutically acceptable composition thereof
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[00182] As used herein, the terms "GCN2-mediated" disorders, diseases, and/or
conditions as
used herein means any disease or other deleterious condition in which GCN2, or
a mutant thereof,
are known to play a role. Accordingly, another embodiment of the present
invention relates to
treating or lessening the severity of one or more diseases in which GCN2, or a
mutant thereof, are
known to play a role.
[00183] In some embodiments, the present invention provides a method for
treating one or more
disorders, diseases, and/or conditions wherein the disorder, disease, or
condition is selected from
the group consisting of inflammatory conditions, immunological conditions,
autoimmune
conditions, allergic conditions, rheumatic conditions, thrombotic conditions,
cancer, infections,
neurodegenerative diseases, degenerative diseases, neuroinflammatory diseases,
cardiovascular
diseases, and metabolic conditions.
[00184] In some embodiments, the cancer to be treated is a solid tumor or a
tumor of the blood
and immune system.
[00185] In some embodiments, the cancer is a solid tumor, wherein the solid
tumor originates
from the group of tumors of the epithelium, the bladder, the stomach, the
kidneys, of head and
neck, the esophagus, the cervix, the thyroid, the intestine, the liver, the
brain, the prostate, the
uro-genital tract, the lymphatic system, the stomach, the larynx, the bones,
including
chondrosarcoma and Ewing sarcoma, germ cells, including embryonal tissue
tumors, and/or the
lung, from the group of monocytic leukemia, lung adenocarcinoma, small-cell
lung carcinomas,
pancreatic cancer, glioblastomas, neurofibroma, angiosarcoma, breast carcinoma
and /or maligna
melanoma.
[00186] In some embodiments, the autoimmune condition is rheumatoid arthritis,
systemic
lupus, multiple sclerosis, psoriasis, Sjogrens syndrome or transplant organ
rejection.
[00187] In some embodiments, the metabolic condition is diabetes.
[00188] In some embodiments, the degenerative disease is osteoarthritis.
[00189] In some embodiments, the inflammatory condition is asthma,
inflammatory bowel
disease, or giant cell arteritis.
[00190] In some embodiments, the cardiovascular disease is an ischemic injury.
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[00191] In some embodiments, the neurodegenerative disease is Alzheimer's
disease, Down's
syndrome, hereditary cerebral hemorrhage with amyloidosis-Dutch Type, cerebral
amyloid
angiopathy, Creutzfeldt-Jakob disease, frontotemporal dementias, Huntington's
disease, or
Parkinson's disease.
[00192] In some embodiments, the infection is caused by leishmania,
mycobacteria, including
M. leprae, M. tuberculosis and/or M. avium, plasmodium, human immunodeficiency
virus, Epstein
Barr virus, Herpes simplex virus, or hepatitis C virus.
[00193] Furthermore, the invention provides the use of a compound according to
the definitions
herein, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof
for the preparation of
a medicament for the treatment of inflammatory conditions, immunological
conditions,
autoimmune conditions, allergic conditions, rheumatic conditions, thrombotic
conditions, cancer,
infections, neurodegenerative diseases, degenerative diseases,
neuroinflammatory diseases,
cardiovascular diseases, or metabolic conditions.
c. Combination Therapies
[00194] Depending upon the particular condition, or disease, to be treated,
additional
therapeutic agents, which are normally administered to treat that condition,
may be administered
in combination with compounds and compositions of this invention. As used
herein, additional
therapeutic agents that are normally administered to treat a particular
disease, or condition, are
known as "appropriate for the disease, or condition, being treated."
[00195] In some embodiments, the present invention provides a method of
treating a disclosed
disease or condition comprising administering to a patient in need thereof an
effective amount of
a compound disclosed herein or a pharmaceutically acceptable salt thereof and
co-administering
simultaneously or sequentially an effective amount of one or more additional
therapeutic agents,
such as those described herein. In some embodiments, the method includes co-
administering one
additional therapeutic agent. In some embodiments, the method includes co-
administering two
additional therapeutic agents. In some embodiments, the combination of the
disclosed compound
and the additional therapeutic agent or agents acts synergistically.
[00196] A compound of the current invention may also be used in combination
with known
therapeutic processes, for example, the administration of hormones or
radiation. In certain
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embodiments, a provided compound is used as a radiosensitizer, especially for
the treatment of
tumors which exhibit poor sensitivity to radiotherapy.
[00197] A compound of the current invention can be administered alone or in
combination with
one or more other therapeutic compounds, possible combination therapy taking
the form of fixed
combinations or the administration of a compound of the invention and one or
more other
therapeutic compounds being staggered or given independently of one another,
or the combined
administration of fixed combinations and one or more other therapeutic
compounds. A compound
of the current invention can besides or in addition be administered especially
for tumor therapy in
combination with chemotherapy, radiotherapy, immunotherapy, phototherapy,
surgical
intervention, or a combination of these. Long-term therapy is equally possible
as is adjuvant
therapy in the context of other treatment strategies, as described above.
Other possible treatments
are therapy to maintain the patient's status after tumor regression, or even
chemopreventive
therapy, for example in patients at risk.
[00198] In certain embodiments, a provided combination, or composition
thereof, is
administered in combination with another therapeutic agent.
[00199] Examples of agents the combinations of this invention may also be
combined with
include, without limitation: treatments for Alzheimer's Disease such as
Aricept and Excelon ;
treatments for HIV such as ritonavir; treatments for Parkinson's Disease such
as L-
DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide,
trihexephendyl,
and amantadine; agents for treating Multiple Sclerosis (MS) such as beta
interferon (e.g., Avonex
and RebiC), Copaxone , and mitoxantrone; treatments for asthma such as
albuterol and
Singulair ; agents for treating schizophrenia such as zyprexa, risperdal,
seroquel, and haloperidol;
anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA,
azathioprine,
cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive
agents such as
cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons,
corticosteroids,
cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as
acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-
convulsants, ion channel
blockers, riluzole, and anti-Parkinsonian agents; agents for treating
cardiovascular disease such as
beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers,
and statins; agents for
treating liver disease such as corticosteroids, cholestyramine, interferons,
and anti-viral agents;
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agents for treating blood disorders such as corticosteroids, anti-leukemic
agents, and growth
factors; agents that prolong or improve pharmacokinetics such as cytochrome
P450 inhibitors (i.e.,
inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketokenozole
and ritonavir), and
agents for treating immunodeficiency disorders such as gamma globulin.
[00200] In certain embodiments, combination therapies of the present
invention, or a
pharmaceutically acceptable composition thereof, are administered in
combination with a
monoclonal antibody or an siRNA therapeutic.
[00201] Those additional agents may be administered separately from a provided
combination
therapy, as part of a multiple dosage regimen. Alternatively, those agents may
be part of a single
dosage form, mixed together with a compound of this invention in a single
composition. If
administered as part of a multiple dosage regime, the two active agents may be
submitted
simultaneously, sequentially or within a period of time from one another
normally within five
hours from one another.
[00202] As used herein, the term "combination," "combined," and related terms
refers to the
simultaneous or sequential administration of therapeutic agents in accordance
with this invention.
For example, a combination of the present invention may be administered with
another therapeutic
agent simultaneously or sequentially in separate unit dosage forms or together
in a single unit
dosage form.
[00203] The amount of one or more other therapeutic agent present in the
compositions of this
invention may be no more than the amount that would normally be administered
in a composition
comprising that therapeutic agent as the only active agent. Preferably the
amount of one or more
other therapeutic agent in the presently disclosed compositions will range
from about 50% to 100%
of the amount normally present in a composition comprising that agent as the
only therapeutically
active agent. In some embodiments, one or more other therapeutic agent is
administered at a dosage
of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about
80%, about 85%,
about 90%, or about 95% of the amount normally administered for that agent. As
used herein, the
phrase "normally administered" means the amount an FDA approved therapeutic
agent is
approvided for dosing per the FDA label insert.
[00204] In one embodiment, the present invention provides a composition
comprising a
compound of formula I and one or more additional therapeutic agents. The
therapeutic agent may
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be administered together with a compound of formula I, or may be administered
prior to or
following administration of a compound of formula I. Suitable therapeutic
agents are described
in further detail below. In certain embodiments, a compound of formula I may
be administered
up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours,
4 hours, 5, hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14
hours, 15 hours, 16
hours, 17 hours, or 18 hours before the therapeutic agent. In other
embodiments, a compound of
formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30
minutes, 1 hour, 2
hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10
hours, 11 hours, 12 hours,
13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the
therapeutic agent.
[00205] In another embodiment, the present invention provides a method of
treating an
inflammatory disease, disorder or condition by administering to a patient in
need thereof a
compound of formula I and one or more additional therapeutic agents. Such
additional therapeutic
agents may be small molecules or recombinant biologic agents and include, for
example,
acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,
ibuprofen,
naproxen, etodolac (Lodineg) and celecoxib, colchicine (Colcrys ),
corticosteroids such as
prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like,
probenecid,
allopurinol, febuxostat (Uloric ), sulfasalazine (Azulfidineg), antimalarials
such as
hydroxychloroquine (Plaquenilg) and chloroquine (Araleng), methotrexate
(Rheumatrex ), gold
salts such as gold thioglucose (Solganalg), gold thiomalate (Myochrysineg) and
auranofin
(Ridaurag), D-penicillamine (Depen or Cuprimineg), azathioprine (Imurang),
cyclophosphamide (Cytoxang), chlorambucil (Leukerang), cyclosporine
(Sandimmuneg),
leflunomide (Aravag) and "anti-TNF" agents such as etanercept (Enbrelg),
infliximab
(Remicadeg), golimumab (Simponig), certolizumab pegol (Cimziag) and adalimumab
(Humirag), "anti-IL-1" agents such as anakinra (Kineretg) and rilonacept
(Arcalystg),
canakinumab (Ilarisg), anti-Jak inhibitors such as tofacitinib, antibodies
such as rituximab
(Rituxang), "anti-T-cell" agents such as abatacept (Orenciag), "anti-IL-6"
agents such as
tocilizumab (Actemrag), diclofenac, cortisone, hyaluronic acid (Synvisc or
Hyalgang),
monoclonal antibodies such as tanezumab, anticoagulants such as heparin
(Calcinparine or
Liquaeming) and warfarin (Coumading), antidiarrheals such as diphenoxylate
(Lomotilg) and
loperamide (Imodiumg), bile acid binding agents such as cholestyramine,
alosetron (Lotronex ),
lubiprostone (Amitizag), laxatives such as Milk of Magnesia, polyethylene
glycol (MiraLax ),
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Dul col axg, Correctolg and Senokotg, anti cholinergi cs or antispasmodics
such as di cycl omine
(Bentylg), Singulairg, beta-2 agonists such as albuterol (Ventoling HFA,
Proventilg HFA),
levalbuterol (Xopenexg), metaproterenol (Alupentg), pirbuterol acetate
(Maxairg), terbutaline
sulfate (Brethaireg), salmeterol xinafoate (Sereventg) and formoterol
(Foradilg), anticholinergic
agents such as ipratropium bromide (Atroventg) and tiotropium (Spirivag),
inhaled
corticosteroids such as beclomethasone dipropionate (Becloventg, Qvarg, and
Vancerilg),
triamcinolone acetonide (Azmacortg), mometasone (Asthmanexg), budesonide
(Pulmocortg),
and flunisolide (Aerobidg), Afviarg, Symbicortg, Dulerag, cromolyn sodium
(Intalg),
methylxanthines such as theophylline (Theo-Durg, Theolairg, Slo-bid ,
Uniphylg, Theo-24g)
and aminophylline, IgE antibodies such as omalizumab (Xolairg), nucleoside
reverse transcriptase
inhibitors such as zidovudine (Retrovirg), abacavir (Ziageng),
abacavir/lamivudine (Epzicomg),
abacavir/lamivudine/zidovudine (Trizivirg), didanosine (Videxg), emtricitabine
(Emtrivag),
lamivudine (Epivirg), lamivudine/zidovudine (Combivirg), stavudine (Zeritg),
and zalcitabine
(Hividg), non-nucleoside reverse transcriptase inhibitors such as delavirdine
(Rescriptorg),
efavirenz (Sustivag), nevairapine (Viramuneg) and etravirine (Intelenceg),
nucleotide reverse
transcriptase inhibitors such as tenofovir (Vireadg), protease inhibitors such
as amprenavir
(Ageneraseg), atazanavir (Reyatazg), darunavir (Prezistag), fosamprenavir
(Lexivag), indinavir
(Crixivang), lopinavir and ritonavir (Kaletrag), nelfinavir (Viraceptg),
ritonavir (Norvirg),
saquinavir (Fortovaseg or Inviraseg), and tipranavir (Aptivusg), entry
inhibitors such as
enfuvirtide (Fuzeong) and maraviroc (Selzentryg), integrase inhibitors such as
raltegravir
(Isentressg), doxorubicin (Hydrodaunorubicing), vincristine (Oncoving),
bortezomib
(Velcadeg), and dexamethasone (Decadron g) in combination with lenalidomide
(Revlimid g),
or any combination(s) thereof.
[00206] In another embodiment, the present invention provides a method of
treating gout
comprising administering to a patient in need thereof a compound of formula I
and one or more
additional therapeutic agents selected from non-steroidal anti-inflammatory
drugs (NSAIDS) such
as aspirin, ibuprofen, naproxen, etodolac (Lodineg) and celecoxib, colchicine
(Colcrysg),
corticosteroids such as prednisone, prednisolone, methylprednisolone,
hydrocortisone, and the
like, probenecid, allopurinol and febuxostat (Uloricg).
[00207] In another embodiment, the present invention provides a method of
treating rheumatoid
arthritis comprising administering to a patient in need thereof a compound of
formula land one or
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more additional therapeutic agents selected from non-steroidal anti-
inflammatory drugs (NSAIDS)
such as aspirin, ibuprofen, naproxen, etodolac (Lodineg) and celecoxib,
corticosteroids such as
prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like,
sulfasalazine
(Azulfidineg), antimalarials such as hydroxychloroquine (Plaquenilg) and
chloroquine
(Araleng), methotrexate (Rheumatrex ), gold salts such as gold thioglucose
(Solganalg), gold
thiomalate (Myochrysineg) and auranofin (Ridaurag), D-penicillamine (Depen or
Cuprimineg), azathioprine (Imurang), cycl ophosp hami de (Cytoxang),
chlorambucil
(Leukerang), cyclosporine (Sandimmuneg), leflunomide (Aravag) and "anti-TNF"
agents such
as etanercept (Enbrelg), infliximab (Remicadeg), golimumab (Simponig),
certolizumab pegol
(Cimziag) and adalimumab (Humirag), "anti-IL-I" agents such as anakinra
(Kineretg) and
rilonacept (Arcalystg), antibodies such as rituximab (Rituxang), "anti-T-cell"
agents such as
abatacept (Orenciag) and "anti-IL-6" agents such as tocilizumab (Actemrag).
[00208] In some embodiments, the present invention provides a method of
treating
osteoarthritis comprising administering to a patient in need thereof a
compound of formula I and
one or more additional therapeutic agents selected from acetaminophen, non-
steroidal anti-
inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac
(Lodineg) and
celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc or Hyalgang) and
monoclonal
antibodies such as tanezumab.
[00209] In some embodiments, the present invention provides a method of
treating lupus
comprising administering to a patient in need thereof a compound of formula I
and one or more
additional therapeutic agents selected from acetaminophen, non-steroidal anti-
inflammatory drugs
(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodineg) and
celecoxib, corticosteroids
such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the
like, antimalarials
such as hydroxychloroquine (Plaquenilg) and chloroquine (Araleng),
cyclophosphamide
(Cytoxang), methotrexate (Rheumatrex ), azathioprine (Imurang) and
anticoagulants such as
heparin (Calcinparine or Liquaeming) and warfarin (Coumading).
[00210] In some embodiments, the present invention provides a method of
treating
inflammatory bowel disease comprising administering to a patient in need
thereof a compound of
formula I and one or more additional therapeutic agents selected from
mesalamine (Asacolg)
sulfasalazine (Azulfidineg), antidiarrheals such as diphenoxylate (Lomotilg)
and loperamide
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(Imodiumg), bile acid binding agents such as cholestyramine, alosetron
(Lotronexg),
lubiprostone (Amitizag), laxatives such as Milk of Magnesia, polyethylene
glycol (MiraLaxg),
Dulcolaxg, Correctolg and Senokotg and anticholinergics or antispasmodics such
as dicyclomine
(Bentylg), anti-TNF therapies, steroids, and antibiotics such as Flagyl or
ciprofloxacin.
[00211] In some embodiments, the present invention provides a method of
treating asthma
comprising administering to a patient in need thereof a compound of formula I
and one or more
additional therapeutic agents selected from Singulairg, beta-2 agonists such
as albuterol
(Vent ling HFA, Proventilg HFA), levalbuterol (Xopenexg), metaproterenol
(Alupentg),
pirbuterol acetate (Maxairg), terbutaline sulfate (Brethaireg), salmeterol
xinafoate (Sereventg)
and formoterol (Foradilg), anticholinergic agents such as ipratropium bromide
(Atroventg) and
tiotropium (Spirivag), inhaled corticosteroids such as prednisone,
prednisolone, beclomethasone
dipropionate (Becloventg, Qvarg, and Vancerilg), triamcinolone acetonide
(Azmacortg),
mometasone (Asthmanexg), budesonide (Pulmocortg), flunisolide (Aerobidg),
Afviarg,
Symbicortg, and Dulerag, cromolyn sodium (Intalg), methylxanthines such as
theophylline
(Theo-Durg, Theolairg, Slo-bid , Uniphylg, Theo-24g) and aminophylline, and
IgE antibodies
such as omalizumab (Xolairg).
[00212] In some embodiments, the present invention provides a method of
treating COPD
comprising administering to a patient in need thereof a compound of formula I
and one or more
additional therapeutic agents selected from beta-2 agonists such as albuterol
(Vent ling HFA,
Proventilg HFA), levalbuterol (Xopenexg), metaproterenol (Alupentg),
pirbuterol acetate
(Maxairg), terbutaline sulfate (Brethaireg), salmeterol xinafoate (Sereventg)
and formoterol
(Foradilg), anticholinergic agents such as ipratropium bromide (Atroventg) and
tiotropium
(Spirivag), methylxanthines such as theophylline (Theo-Durg, Theolairg, Slo-
bid , Uniphylg,
Theo-24g) and aminophylline, inhaled corticosteroids such as prednisone,
prednisolone,
beclomethasone di propi onate (B ecloventg, Qvarg, and Vane erilg), tri am
cinol one acetonide
(Azmacortg), mometasone (Asthmanexg), budesonide (Pulmocortg), flunisolide
(Aerobidg),
Afviarg, Symbicortg, and Dulerag,
[00213] In some embodiments, the present invention provides a method of
treating HIV
comprising administering to a patient in need thereof a compound of formula I
and one or more
additional therapeutic agents selected from nucleoside reverse transcriptase
inhibitors such as
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zidovudine (Retrovirg), abacavir (Ziageng),
ab acavir/lamivudine (Epzicomg),
abacavir/lamivudine/zidovudine (Trizivirg), didanosine (Videxg), emtricitabine
(Emtrivag),
lamivudine (Epivirg), lamivudine/zidovudine (Combivirg), stavudine (Zeritg),
and zalcitabine
(Hividg), non-nucleoside reverse transcriptase inhibitors such as delavirdine
(Rescriptorg),
efavirenz (Sustivag), nevairapine (Viramuneg) and etravirine (Intelenceg),
nucleotide reverse
transcriptase inhibitors such as tenofovir (Vireadg), protease inhibitors such
as amprenavir
(Ageneraseg), atazanavir (Reyatazg), darunavir (Prezistag), fosamprenavir
(Lexivag), indinavir
(Crixivang), lopinavir and ritonavir (Kaletrag), nelfinavir (Viraceptg),
ritonavir (Norvirg),
saquinavir (Fortovaseg or Inviraseg), and tipranavir (Aptivusg), entry
inhibitors such as
enfuvirtide (Fuzeong) and maraviroc (Selzentryg), integrase inhibitors such as
raltegravir
(Isentressg), and combinations thereof
[00214] In another embodiment, the present invention provides a method of
treating a
hematological malignancy comprising administering to a patient in need thereof
a compound of
formula I and one or more additional therapeutic agents selected from
rituximab (Rituxang),
cyclophosphamide (Cytoxang), doxorubicin (Hydrodaunorubicing), vincristine
(Oncoving),
prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK
inhibitor, a TYK2
inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.
[00215] In another embodiment, the present invention provides a method of
treating a solid
tumor comprising administering to a patient in need thereof a compound of
formula I and one or
more additional therapeutic agents selected from rituximab (Rituxang),
cyclophosphamide
(Cytoxang), doxorubicin (Hydrodaunorubicing), vincristine (Oncoving),
prednisone, a
hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2
inhibitor, a PI3K
inhibitor, a SYK inhibitor, and combinations thereof
[00216] In another embodiment, the present invention provides a method of
treating a
hematological malignancy comprising administering to a patient in need thereof
a compound of
formula I and a Hedgehog (Hh) signaling pathway inhibitor. In some
embodiments, the
hematological malignancy is DLBCL (Ramirez et at "Defining causative factors
contributing in
the activation of hedgehog signaling in diffuse large B-cell lymphoma" Leuk.
Res. (2012),
published online July 17, and incorporated herein by reference in its
entirety).
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[00217] In another embodiment, the present invention provides a method of
treating diffuse
large B-cell lymphoma (DLBCL) comprising administering to a patient in need
thereof a
compound of formula I and one or more additional therapeutic agents selected
from rituximab
(Rituxang), cyclophosphamide (Cytoxang), doxorubicin (Hydrodaunorubicing),
vincristine
(Oncoving), prednisone, a hedgehog signaling inhibitor, and combinations
thereof.
[00218] In another embodiment, the present invention provides a method of
treating multiple
myeloma comprising administering to a patient in need thereof a compound of
formula I and one
or more additional therapeutic agents selected from bortezomib (Velcadeg), and
dexamethasone
(Decadrong), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK
inhibitor, a TYK2
inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide
(Revlimidg).
[00219] In another embodiment, the present invention provides a method of
treating
Waldenstrom's macroglobulinemia comprising administering to a patient in need
thereof a
compound of formula I and one or more additional therapeutic agents selected
from chlorambuci
(Leukerang), cyclophosphamide (Cytoxang, Neosarg), fluclarabine (Flu(larag),
cladribine
(Leustating), rituxiinab (Rituxang), a hedgehog signaling inhibitor, a BTK
inhibitor, a JAK/pan-
JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.
[00220] In some embodiments; the present invention provides a method of
treating Alzheimer's
disease comprising administering to a patient n need thereof a compound of
formula I and one or
more additional therapeutic agents selected from donepezil (Ariceptc)),
rivastigmine (Excelonc)),
galantamine (Razadynec)), tacrine (Cognex(9), and memantine (Namenda ).
[00221] In another embodiment, the present invention provides a method of
treating organ
transplant rejection or graft vs host disease comprising administering to a
patient in need thereof
a compound of formula I and one or more additional therapeutic agents selected
from a steroid,
cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor, a BTK
inhibitor, a JAK/pan-JAK
inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.
[00222] In another embodiment, the present invention provides a method of
treating or
lessening the severity of a disease comprising administering to a patient in
need thereof a
compound of formula I and a BTK inhibitor, wherein the disease is selected
from inflammatory
bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis,
idiopathic
thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis,
osteoarthritis, Still's
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disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto' s
thyroiditis, Ord's thyroiditis,
Graves' disease, autoimmune thyroiditis, Sjogren' s syndrome, multiple
sclerosis, systemic
sclerosis, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated
encephalomyelitis,
Addison' s disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis,
antiphospholipid
antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune
gastritis, pernicious
anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic
purpura, optic
neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome,
Takayasu's arteritis, temporal
arteritis, warm autoimmune hemolytic anemia, Wegener' s granulomatosis,
psoriasis, alopecia
universalis, Behcet's disease, chronic fatigue, dysautonomia, membranous
glomerulonephropathy,
endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid,
neuromyotonia,
scleroderma, vulvodynia, a hyperproliferative disease, rejection of
transplanted organs or tissues,
Acquired Immunodeficiency Syndrome (AIDS, also known as HIV), type 1 diabetes,
graft versus
host disease, transplantation, transfusion, anaphylaxis, allergies (e.g.,
allergies to plant pollens,
latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites,
or cockroach calyx),
type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and
atopic dermatitis, asthma,
appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis,
bronchitis, bursitis,
cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis,
conjunctivitis, Crohn's disease,
cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis,
endocarditis, endometritis,
enteritis, enterocolitis, epicondylitis, epi di dymiti s, fasciitis,
fibrositis, gastritis, gastroenteritis,
Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin
A nephropathy,
interstitial lung disease, laryngitis, mastitis, meningitis, myelitis
myocarditis, myositis, nephritis,
oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,
peritonitis, pharyngitis,
pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,
prostatitis, pyelonephritis,
rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis,
tonsillitis, ulcerative colitis, uveitis,
vaginitis, vasculitis, or vulvitis, B-cell proliferative disorder, e.g.,
diffuse large B cell lymphoma,
follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic
leukemia, acute
lymphocytic leukemia, B-cell prolymphocytic
leukemia, lymphoplasmacyti c
lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma,
multiple
myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's
lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal
marginal zone B
cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell
lymphoma, intravascular
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large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia,
or
lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of the
mast cells (e.g.,
mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis),
bone cancer,
colorectal cancer, pancreatic cancer, diseases of the bone and joints
including, without limitation,
rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing
spondylitis,
psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's
syndrome, systemic sclerosis,
osteoporosis, bone cancer, bone metastasis, a thromboembolic disorder, (e.g.,
myocardial infarct,
angina pectoris, reocclusion after angioplasty, restenosis after angioplasty,
reocclusion after
aortocoronary bypass, restenosis after aortocoronary bypass, stroke,
transitory ischemia, a
peripheral arterial occlusive disorder, pulmonary embolism, deep venous
thrombosis),
inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis,
encephalitis,
meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis,
gastritis, enteritis, dermatitis,
gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia,
psoriasis, allergy,
Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's
disease, tissue graft
rejection, hyperacute rejection of transplanted organs, asthma, allergic
rhinitis, chronic obstructive
pulmonary disease (COPD), autoimmune polyglandular disease (also known as
autoimmune
polyglandular syndrome), autoimmune alopecia, pernicious anemia,
glomerulonephritis,
dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune
hemolytic and
thromb ocytopenic states, Goodpasture' s syndrome, atherosclerosis, Addison' s
disease,
Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic
lupus erythematosus
(SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis,
osteoarthritis, chronic idiopathic
thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis,
Hashimoto's
thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo,
autoimmune hypopituitarism,
Guillain-Barre syndrome, Behcet's disease, scleraderma, mycosis fungoides,
acute inflammatory
responses (such as acute respiratory distress syndrome and
ischemia/reperfusion injury), and
Graves' disease.
[00223] In another embodiment, the present invention provides a method of
treating or
lessening the severity of a disease comprising administering to a patient in
need thereof a
compound of formula I and a PI3K inhibitor, wherein the disease is selected
from a cancer, a
neurodegenative disorder, an angiogenic disorder, a viral disease, an
autoimmune disease, an
inflammatory disorder, a hormone-related disease, conditions associated with
organ
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transplantation, immunodeficiency disorders, a destructive bone disorder, a
proliferative disorder,
an infectious disease, a condition associated with cell death, thrombin-
induced platelet
aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia
(CLL), liver
disease, pathologic immune conditions involving T cell activation, a
cardiovascular disorder, and
a CNS disorder.
[00224] In another embodiment, the present invention provides a method of
treating or
lessening the severity of a disease comprising administering to a patient in
need thereof a
compound of formula I and a PI3K inhibitor, wherein the disease is selected
from benign or
malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal
cell carcinoma (RCC)),
liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries,
colon, rectum, prostate,
pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract,
esophagus, larynx, skin,
bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or
gastrointestinal
cancer, especially colon carcinoma or colorectal adenoma or a tumor of the
neck and head, an
epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a
neoplasia of epithelial
character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma,
large cell
carcinoma, non-small-cell lung carcinoma, lymphomas, (including, for example,
non-Hodgkin's
Lymphoma (NHL) and Hodgkin's lymphoma (also termed Hodgkin's or Hodgkin's
disease)), a
mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary
carcinoma,
seminoma, melanoma, or a leukemia, diseases include Cowden syndrome, Lhermitte-
Dudos
disease and Bannayan-Zonana syndrome, or diseases in which the PI3K/PKB
pathway is
aberrantly activated, asthma of whatever type or genesis including both
intrinsic (non-allergic)
asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe
asthma, bronchitic
asthma, exercise-induced asthma, occupational asthma and asthma induced
following bacterial
infection, acute lung injury (ALT), adult/acute respiratory distress syndrome
(ARDS), chronic
obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including
chronic
bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation
of airways
hyperreactivity consequent to other drug therapy, in particular other inhaled
drug therapy,
bronchitis of whatever type or genesis including, but not limited to, acute,
arachidic, catarrhal,
croupus, chronic or phthinoid bronchitis, pneumoconiosis (an inflammatory,
commonly
occupational, disease of the lungs, frequently accompanied by airways
obstruction, whether
chronic or acute, and occasioned by repeated inhalation of dusts) of whatever
type or genesis,
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including, for example, aluminosis, anthracosis, asbestosis, chalicosis,
ptilosis, siderosis, silicosis,
tabacosis and byssinosis, Loffler's syndrome, eosinophilic, pneumonia,
parasitic (in particular
metazoan) infestation (including tropical eosinophilia), bronchopulmonary
aspergillosis,
polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic
granuloma and eosinophil-
related disorders affecting the airways occasioned by drug-reaction,
psoriasis, contact dermatitis,
atopic dermatitis, alopecia areata, erythema multiforma, dermatitis
herpetiformis, scleroderma,
vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus
erythematosus, pemphi sus,
epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca,
and vernal
conjunctivitis, diseases affecting the nose including allergic rhinitis, and
inflammatory disease in
which autoimmune reactions are implicated or having an autoimmune component or
etiology,
including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic
anemia, pure red
cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus,
rheumatoid arthritis,
polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic
active hepatitis,
myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune
inflammatory bowel
disease (e.g. ulcerative colitis and Crohn's disease), endocrine
opthalmopathy, Grave's disease,
sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple
sclerosis, primary biliary
cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and
vernal
keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and
glomerulonephritis (with and
without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or
minal change
nephropathy, restenosis, cardiomegaly, atherosclerosis, myocardial infarction,
ischemic stroke and
congestive heart failure, Alzheimer's disease, Parkinson's disease,
amyotrophic lateral sclerosis,
Huntington's disease, and cerebral ischemia, and neurodegenerative disease
caused by traumatic
injury, glutamate neurotoxicity and hypoxia.
[00225] The compounds and compositions, according to the method of the present
invention,
may be administered using any amount and any route of administration effective
for treating or
lessening the severity of a cancer, an autoimmune disorder, a proliferative
disorder, an
inflammatory disorder, a neurodegenerative or neurological disorder,
schizophrenia, a bone-
related disorder, liver disease, or a cardiac disorder. The exact amount
required will vary from
subject to subject, depending on the species, age, and general condition of
the subject, the severity
of the infection, the particular agent, its mode of administration, and the
like. Compounds of the
invention are preferably formulated in dosage unit form for ease of
administration and uniformity
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of dosage. The expression "dosage unit form" as used herein refers to a
physically discrete unit of
agent appropriate for the patient to be treated. It will be understood,
however, that the total daily
usage of the compounds and compositions of the present invention will be
decided by the attending
physician within the scope of sound medical judgment. The specific effective
dose level for any
particular patient or organism will depend upon a variety of factors including
the disorder being
treated and the severity of the disorder; the activity of the specific
compound employed; the
specific composition employed; the age, body weight, general health, sex and
diet of the patient;
the time of administration, route of administration, and rate of excretion of
the specific compound
employed; the duration of the treatment; drugs used in combination or
coincidental with the
specific compound employed, and like factors well known in the medical arts.
The term "patient",
as used herein, means an animal, preferably a mammal, and most preferably a
human.
[00226] Pharmaceutically acceptable compositions of this invention can be
administered to
humans and other animals orally, rectally, parenterally, intracisternally,
intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops), bucally, as
an oral or nasal spray,
or the like, depending on the severity of the infection being treated. In
certain embodiments, the
compounds of the invention may be administered orally or parenterally at
dosage levels of about
0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25
mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[00227] Liquid dosage forms for oral administration include, but are not
limited to,
pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions,
syrups and
elixirs. In addition to the active compounds, the liquid dosage forms may
contain inert diluents
commonly used in the art such as, for example, water or other solvents,
solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
acetate, benzyl alcohol,
benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide,
oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures
thereof Besides inert
diluents, the oral compositions can also include adjuvants such as wetting
agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[00228] Injectable preparations, for example, sterile injectable aqueous or
oleaginous
suspensions may be formulated according to the known art using suitable
dispersing or wetting
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agents and suspending agents. The sterile injectable preparation may also be a
sterile injectable
solution, suspension or emulsion in a nontoxic parenterally acceptable diluent
or solvent, for
example, as a solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be
employed are water, Ringer's solution, U. S.P. and isotonic sodium chloride
solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or suspending
medium. For this purpose
any bland fixed oil can be employed including synthetic mono- or diglycerides.
In addition, fatty
acids such as oleic acid are used in the preparation of injectables.
[00229] Injectable formulations can be sterilized, for example, by
filtration through a bacterial-
retaining filter, or by incorporating sterilizing agents in the form of
sterile solid compositions
which can be dissolved or dispersed in sterile water or other sterile
injectable medium prior to use.
[00230] In order to prolong the effect of a compound of the present invention,
it is often
desirable to slow the absorption of the compound from subcutaneous or
intramuscular injection.
This may be accomplished by the use of a liquid suspension of crystalline or
amorphous material
with poor water solubility. The rate of absorption of the compound then
depends upon its rate of
dissolution that, in turn, may depend upon crystal size and crystalline form.
Alternatively, delayed
absorption of a parenterally administered compound form is accomplished by
dissolving or
suspending the compound in an oil vehicle. Injectable depot forms are made by
forming
microencapsule matrices of the compound in biodegradable polymers such as
polylactide-
polyglycolide. Depending upon the ratio of compound to polymer and the nature
of the particular
polymer employed, the rate of compound release can be controlled. Examples of
other
biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable
formulations are also prepared by entrapping the compound in liposomes or
microemulsions that
are compatible with body tissues.
[00231] Compositions for rectal or vaginal administration are preferably
suppositories which
can be prepared by mixing the compounds of this invention with suitable non-
irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a suppository wax
which are solid at
ambient temperature but liquid at body temperature and therefore melt in the
rectum or vaginal
cavity and release the active compound.
[00232] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and
granules. In such solid dosage forms, the active compound is mixed with at
least one inert,
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pharmaceutically acceptable excipient or carrier such as sodium citrate or
dicalcium phosphate
and/or a) fillers or extenders such as starches, lactose, sucrose, glucose,
mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol,
d) disintegrating
agents such as agar--agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such as
paraffin, f) absorption
accelerators such as quaternary ammonium compounds, g) wetting agents such as,
for example,
cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i)
lubricants such as talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium
lauryl sulfate, and mixtures thereof In the case of capsules, tablets and
pills, the dosage form may
also comprise buffering agents.
[00233] Solid compositions of a similar type may also be employed as
fillers in soft and hard-
filled gelatin capsules using such excipients as lactose or milk sugar as well
as high molecular
weight polyethylene glycols and the like. The solid dosage forms of tablets,
dragees, capsules,
pills, and granules can be prepared with coatings and shells such as enteric
coatings and other
coatings well known in the pharmaceutical formulating art. They may optionally
contain
opacifying agents and can also be of a composition that they release the
active ingredient(s) only,
or preferentially, in a certain part of the intestinal tract, optionally, in a
delayed manner. Examples
of embedding compositions that can be used include polymeric substances and
waxes. Solid
compositions of a similar type may also be employed as fillers in soft and
hard-filled gelatin
capsules using such excipients as lactose or milk sugar as well as high
molecular weight
polethylene glycols and the like.
[00234] The active compounds can also be in micro-encapsulated form with one
or more
excipients as noted above. The solid dosage forms of tablets, dragees,
capsules, pills, and granules
can be prepared with coatings and shells such as enteric coatings, release
controlling coatings and
other coatings well known in the pharmaceutical formulating art. In such solid
dosage forms the
active compound may be admixed with at least one inert diluent such as
sucrose, lactose or starch.
Such dosage forms may also comprise, as is normal practice, additional
substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such a magnesium
stearate and
microcrystalline cellulose. In the case of capsules, tablets and pills, the
dosage forms may also
comprise buffering agents. They may optionally contain opacifying agents and
can also be of a
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composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of embedding
compositions that can be
used include polymeric substances and waxes.
[00235] Dosage forms for topical or transdermal administration of a compound
of this invention
include ointments, pastes, creams, lotions, gels, powders, solutions, sprays,
inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable
carrier and any needed preservatives or buffers as may be required. Ophthalmic
formulation, ear
drops, and eye drops are also contemplated as being within the scope of this
invention.
Additionally, the present invention contemplates the use of transdermal
patches, which have the
added advantage of providing controlled delivery of a compound to the body.
Such dosage forms
can be made by dissolving or dispensing the compound in the proper medium.
Absorption
enhancers can also be used to increase the flux of the compound across the
skin. The rate can be
controlled by either providing a rate controlling membrane or by dispersing
the compound in a
polymer matrix or gel.
[00236] According to one embodiment, the invention relates to a method of
inhibiting protein
kinase activity in a biological sample comprising the step of contacting said
biological sample with
a compound of this invention, or a composition comprising said compound.
[00237] According to another embodiment, the invention relates to a method of
inhibiting
GCN2, or a mutant thereof, activity in a biological sample comprising the step
of contacting said
biological sample with a compound of this invention, or a composition
comprising said compound.
[0100] The term "biological sample", as used herein, includes, without
limitation, cell cultures or
extracts thereof biopsied material obtained from a mammal or extracts thereof;
and blood, saliva,
urine, feces, semen, tears, or other body fluids or extracts thereof
[00238] Inhibition of protein kinase, or a GCN2 protein kinase, or a mutant
thereof, activity in
a biological sample is useful for a variety of purposes that are known to one
of skill in the art.
Examples of such purposes include, but are not limited to, blood transfusion,
organ-
transplantation, biological specimen storage, and biological assays.
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[00239] Another embodiment of the present invention relates to a method of
inhibiting protein
kinase activity in a patient comprising the step of administering to said
patient a compound of the
present invention, or a composition comprising said compound.
[00240] According to another embodiment, the invention relates to a method of
inhibiting
GCN2, or a mutant thereof, activity in a patient comprising the step of
administering to said patient
a compound of the present invention, or a composition comprising said
compound. In other
embodiments, the present invention provides a method for treating a disorder
mediated by GCN2,
or a mutant thereof, in a patient in need thereof, comprising the step of
administering to said patient
a compound according to the present invention or pharmaceutically acceptable
composition
thereof. Such disorders are described in detail herein.
[00241] Depending upon the particular condition, or disease, to be treated,
additional
therapeutic agents that are normally administered to treat that condition, may
also be present in the
compositions of this invention. As used herein, additional therapeutic agents
that are normally
administered to treat a particular disease, or condition, are known as
"appropriate for the disease,
or condition, being treated."
[00242] A compound of the current invention may also be used to advantage in
combination
with other antiproliferative compounds. Such antiproliferative compounds
include, but are not
limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors;
topoisomerase II
inhibitors; microtubule active compounds; alkylating compounds; histone
deacetylase inhibitors;
compounds which induce cell differentiation processes; cyclooxygenase
inhibitors; MMI)
inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds;
compounds
targeting/decreasing a protein or lipid kinase activity and further anti-
angiogenic compounds;
compounds which target, decrease or inhibit the activity of a protein or lipid
phosphatase;
gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors;
matrix
metalloproteinase inhibitors; bisphosphonates; biological response modifiers;
antiproliferative
antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms;
telomerase inhibitors;
proteasome inhibitors; compounds used in the treatment of hematologic
malignancies; compounds
which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such
as 17-AAG (17-
allyl aminogel danamycin, NSC330507),
17-DMAG (17-dimethyl aminoethyl amino-17-
demethoxy-geldanamycin, N5C707545), IPI-504, CNF1010, CNF2024, CNF1010 from
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Conforma Therapeutics; temozolomide (Temoda1 ); kinesin spindle protein
inhibitors, such as
SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from
CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244
from
AstraZeneca, PD181461 from Pfizer and leucovorin. The term "aromatase
inhibitor" as used herein
relates to a compound which inhibits estrogen production, for instance, the
conversion of the
substrates androstenedione and testosterone to estrone and estradiol,
respectively. The term
includes, but is not limited to steroids, especially atamestane, exemestane
and formestane and, in
particular, non-steroids, especially aminoglutethimide, roglethimide,
pyridoglutethimide,
trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and
letrozole. Exemestane
is marketed under the trade name AromasinTM. Formestane is marketed under the
trade name
LentaronTM. Fadrozole is marketed under the trade name AfemaTM. Anastrozole is
marketed under
the trade name ArimidexTM. Letrozole is marketed under the trade names
FemaraTM or FemarTM.
Aminoglutethimide is marketed under the trade name OrimetenTM. A combination
of the invention
comprising a chemotherapeutic agent which is an aromatase inhibitor is
particularly useful for the
treatment of hormone receptor positive tumors, such as breast tumors.
[00243] The term "antiestrogen" as used herein relates to a compound which
antagonizes the
effect of estrogens at the estrogen receptor level. The term includes, but is
not limited to tamoxifen,
fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed
under the trade name
NolvadexTM. Raloxifene hydrochloride is marketed under the trade name
EvistaTM. Fulvestrant can
be administered under the trade name FaslodexTM. A combination of the
invention comprising a
chemotherapeutic agent which is an anti estrogen is particularly useful for
the treatment of estrogen
receptor positive tumors, such as breast tumors.
[00244] The term "anti-androgen" as used herein relates to any substance which
is capable of
inhibiting the biological effects of androgenic hormones and includes, but is
not limited to,
bicalutamide (CasodexTm). The term "gonadorelin agonist" as used herein
includes, but is not
limited to abarelix, goserelin and goserelin acetate. Goserelin can be
administered under the trade
name ZoladexTM.
[00245] In some embodiments, one or more other therapeutic agent is an
androgen receptor
inhibitor. Approved androgen receptor inhibitors useful in the present
invention include
enzalutamide (Xtandig, Astellas/Medivation); approved inhibitors of androgen
synthesis include
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abiraterone (Zytigag, Centocor/Ortho); approved antagonist of gonadotropin-
releasing hormone
(GnRH) receptor (degaralix, Firmagong, Ferring Pharmaceuticals).
[00246] In some embodiments, one or more other therapeutic agent is a
selective estrogen
receptor modulator (SERM), which interferes with the synthesis or activity of
estrogens.
Approved SERMs useful in the present invention include raloxifene (Evistag,
Eli Lilly).
[00247] The term "topoisomerase I inhibitor" as used herein includes, but
is not limited to
topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-
nitrocamptothecin and the
macromolecular camptothecin conjugate PNU-166148. Irinotecan can be
administered, e.g. in the
form as it is marketed, e.g. under the trademark CamptosarTM. Topotecan is
marketed under the
trade name HycamptinTM.
[00248] The term "topoisomerase II inhibitor" as used herein includes, but
is not limited to the
anthracyclines such as doxorubicin (including liposomal formulation, such as
CaelyxTm),
daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones
mitoxantrone and
losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is
marketed under
the trade name EtopophosTM. Teniposide is marketed under the trade name VM 26-
Bristol
Doxorubicin is marketed under the trade name Acriblastin TM or AdriamycinTM.
Epirubicin is
marketed under the trade name FarmorubicinTM. Idarubicin is marketed. under
the trade name
ZavedosTM. Mitoxantrone is marketed under the trade name Novantron.
[00249] The term "microtubule active agent" relates to microtubule
stabilizing, microtubule
destabilizing compounds and microtublin polymerization inhibitors including,
but not limited to
taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as
vinblastine or vinblastine
sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides;
cochicine and
epothilones and derivatives thereof Paclitaxel is marketed under the trade
name TaxolTm.
Docetaxel is marketed under the trade name TaxotereTm. Vinblastine sulfate is
marketed under the
trade name Vinblastin R.PTM. Vincristine sulfate is marketed under the trade
name FarmistinTM.
[00250] The term "alkylating agent" as used herein includes, but is not
limited to,
cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
Cyclophosphamide
is marketed under the trade name CyclostinTm. Ifosfamide is marketed under the
trade name
HoloxanTM
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[00251] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates
to compounds
which inhibit the histone deacetylase and which possess antiproliferative
activity. This includes,
but is not limited to, suberoylanilide hydroxamic acid (SAHA).
[00252] The term "antineoplastic antimetabolite" includes, but is not
limited to, 5-fluorouracil
or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-
azacytidine and
decitabine, methotrexate and edatrexate, and folic acid antagonists such as
pemetrexed.
Capecitabine is marketed under the trade name XelodaTM. Gemcitabine is
marketed under the trade
name GemzarTM.
[00253] The term "platin compound" as used herein includes, but is not
limited to, carboplatin,
cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered,
e.g., in the form as it is
marketed, e.g. under the trademark CarboplatTM. Oxaliplatin can be
administered, e.g., in the form
as it is marketed, e.g. under the trademark EloxatinTM.
[00254] The term "compounds targeting/decreasing a protein or lipid kinase
activity; or a
protein or lipid phosphatase activity; or further anti-angiogenic compounds"
as used herein
includes, but is not limited to, protein tyrosine kinase and/or serine and/or
threonine kinase
inhibitors or lipid kinase inhibitors, such as a) compounds targeting,
decreasing or inhibiting the
activity of the platelet-derived growth factor-receptors (PDGFR), such as
compounds which target,
decrease or inhibit the activity of PDGFR, especially compounds which inhibit
the PDGF receptor,
such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101,
SU6668 and GFB-
111; b) compounds targeting, decreasing or inhibiting the activity of the
fibroblast growth factor-
receptors (FGFR); c) compounds targeting, decreasing or inhibiting the
activity of the insulin-like
growth factor receptor I (IGF-IR), such as compounds which target, decrease or
inhibit the activity
of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I
receptor, or antibodies
that target the extracellular domain of IGF-I receptor or its growth factors;
d) compounds targeting,
decreasing or inhibiting the activity of the Trk receptor tyrosine kinase
family, or ephrin B4
inhibitors; e) compounds targeting, decreasing or inhibiting the activity of
the AxI receptor
tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the
activity of the Ret
receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the
activity of the
Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting,
decreasing or
inhibiting the activity of the C-kit receptor tyrosine kinases, which are part
of the PDGFR family,
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such as compounds which target, decrease or inhibit the activity of the c-Kit
receptor tyrosine
kinase family, especially compounds which inhibit the c-Kit receptor, such as
imatinib; i)
compounds targeting, decreasing or inhibiting the activity of members of the c-
Abl family, their
gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds
which target
decrease or inhibit the activity of c-Abl family members and their gene fusion
products, such as
an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib
(AMN107); PD180970;
AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j)
compounds
targeting, decreasing or inhibiting the activity of members of the protein
kinase C (PKC) and Raf
family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,
PDK1,
PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the
cyclin-
dependent kinase family (CDK) including staurosporine derivatives, such as
midostaurin;
examples of further compounds include UCN-01, safingol, BAY 43-9006,
Bryostatin 1,
Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521;
LY333531/LY379196;
isochinoline compounds; FTIs; PD184352 or QAN697 (a P 13K inhibitor) or AT7519
(CDK
inhibitor); k) compounds targeting, decreasing or inhibiting the activity of
protein-tyrosine kinase
inhibitors, such as compounds which target, decrease or inhibit the activity
of protein-tyrosine
kinase inhibitors include imatinib mesyl ate (GleevecTM) or tyrphostin such as
Tyrphostin A23/RG-
50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490;
Tyrphostin B44;
Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556,
AG957 and
adaphostin (4-{[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl
ester; NSC
680410, adaphostin); 1) compounds targeting, decreasing or inhibiting the
activity of the epidermal
growth factor family of receptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4
as homo- or
heterodimers) and their mutants, such as compounds which target, decrease or
inhibit the activity
of the epidermal growth factor receptor family are especially compounds,
proteins or antibodies
which inhibit members of the EGF receptor tyrosine kinase family, such as EGF
receptor, ErbB2,
ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM
105180;
trastuzumab (HerceptinTm), cetuximab (ErbituxTm), Iressa, Tarceva, OSI-774, C1-
1033, EKB-569,
GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-
[2,3-d]pyrimidine
derivatives; m) compounds targeting, decreasing or inhibiting the activity of
the c-Met receptor,
such as compounds which target, decrease or inhibit the activity of c-Met,
especially compounds
which inhibit the kinase activity of c-Met receptor, or antibodies that target
the extracellular
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domain of c-Met or bind to HGF, n) compounds targeting, decreasing or
inhibiting the kinase
activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-
JAK),
including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib,
momelotinib, VX-509,
AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting,
decreasing or
inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited
to ATU-027, SF-1126,
DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-
4691502, BYL-719,
dactolisib, XL-147, XL-765, and idelalisib; and; and q) compounds targeting,
decreasing or
inhibiting the signaling effects of hedgehog protein (Hh) or smoothened
receptor (SMO) pathways,
including but not limited to cyclopamine, vismodegib, itraconazole,
erismodegib, and IPI-926
(saridegib).
[00255] The term "PI3K inhibitor" as used herein includes, but is not limited
to compounds
having inhibitory activity against one or more enzymes in the
phosphatidylinosito1-3-kinase
family, including, but not limited to PI3Ka, PI3Ky, PI3K6, PI3K13, PI3K-C2a,
PI3K-C213, PI3K-
C2y, Vps34, p110-a, p110-0, p110-y, p110-6, p85-a, p85-0, p55-y, p150, p101,
and p87. Examples
of PI3K inhibitors useful in this invention include but are not limited to ATU-
027, SF-1126, DS-
7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502,
BYL-719,
dactolisib, XL-147, XL-765, and idelalisib.
[00256] The term "BTK inhibitor" as used herein includes, but is not limited
to compounds
having inhibitory activity against Bruton' s Tyrosine Kinase (BTK), including,
but not limited to
AVL-292 and ibrutinib.
[00257] The term "SYK inhibitor" as used herein includes, but is not limited
to compounds
having inhibitory activity against spleen tyrosine kinase (SYK), including but
not limited to PRT-
062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib
[00258] Further examples of BTK inhibitory compounds, and conditions treatable
by such
compounds in combination with compounds of this invention can be found in
W02008039218
and W02011090760, the entirety of which are incorporated herein by reference.
[00259] Further examples of SYK inhibitory compounds, and conditions treatable
by such
compounds in combination with compounds of this invention can be found in
W02003063794,
W02005007623, and W02006078846, the entirety of which are incorporated herein
by reference.
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[00260] Further examples of PI3K inhibitory compounds, and conditions
treatable by such
compounds in combination with compounds of this invention can be found in
W02004019973,
W02004089925, W02007016176, US8138347, W02002088112, W02007084786,
W02007129161, W02006122806, W02005113554, and W02007044729 the entirety of
which
are incorporated herein by reference.
[00261] Further examples of JAK inhibitory compounds, and conditions treatable
by such
compounds in combination with compounds of this invention can be found in
W02009114512,
W02008109943, W02007053452, W02000142246, and W02007070514, the entirety of
which
are incorporated herein by reference.
[00262] Further anti-angiogenic compounds include compounds having another
mechanism for
their activity, e.g. unrelated to protein or lipid kinase inhibition e.g.
thalidomide (ThalomidTm) and
TNP-470.
[00263] Examples of proteasome inhibitors useful for use in combination with
compounds of
the invention include, but are not limited to bortezomib, disulfiram,
epigallocatechin-3-gallate
(EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.
[00264] Compounds which target, decrease or inhibit the activity of a protein
or lipid
phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25,
such as okadaic acid
or a derivative thereof
[00265] Compounds which induce cell differentiation processes include, but are
not limited to,
retinoic acid, a- y- or 6- tocopherol or a- y- or 6-tocotrienol.
[00266] The term cyclooxygenase inhibitor as used herein includes, but is not
limited to, Cox-
2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and
derivatives, such as celecoxib
(CelebrexTm), rofecoxib (VioxxTm), etoricoxib, valdecoxib or a 5-alkyl-2-
arylaminophenylacetic
acid, such as 5-methy1-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid,
lumiracoxib.
[00267] The term "bisphosphonates" as used herein includes, but is not
limited to, etridonic,
clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and
zoledronic acid. Etridonic
acid is marketed under the trade name DidronelTM. Clodronic acid is marketed
under the trade
name BonefosTM. Tiludronic acid is marketed under the trade name SkelidTM.
Pamidronic acid is
marketed under the trade name ArediaTM. Alendronic acid is marketed under the
trade name
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FosamaxTM. Ibandronic acid is marketed under the trade name BondranatTM.
Risedronic acid is
marketed under the trade name ActonelTM. Zoledronic acid is marketed under the
trade name
ZometaTM. The term "mTOR inhibitors" relates to compounds which inhibit the
mammalian target
of rapamycin (mTOR) and which possess antiproliferative activity such as
sirolimus
(Rapamuneg), everolimus (CerticanTm), CCI-779 and ABT578.
[00268] The term "heparanase inhibitor" as used herein refers to compounds
which target,
decrease or inhibit heparin sulfate degradation. The term includes, but is not
limited to, PI-88. The
term "biological response modifier" as used herein refers to a lymphokine or
interferons.
[00269] The term "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras,
or N-Ras, as
used herein refers to compounds which target, decrease or inhibit the
oncogenic activity of Ras;
for example, a "farnesyl transferase inhibitor" such as L-744832, DK8G557 or
R115777
(ZarnestraTm). The term "telomerase inhibitor" as used herein refers to
compounds which target,
decrease or inhibit the activity of telomerase. Compounds which target,
decrease or inhibit the
activity of telomerase are especially compounds which inhibit the telomerase
receptor, such as
telomestatin.
[00270] The term "methionine aminopeptidase inhibitor" as used herein refers
to compounds
which target, decrease or inhibit the activity of methionine aminopeptidase.
Compounds which
target, decrease or inhibit the activity of methionine aminopeptidase include,
but are not limited
to, bengamide or a derivative thereof.
[00271] The term "proteasome inhibitor" as used herein refers to compounds
which target,
decrease or inhibit the activity of the proteasome. Compounds which target,
decrease or inhibit the
activity of the proteasome include, but are not limited to, Bortezomib
(VelcadeTM) and MLN 341.
[00272] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as
used herein
includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic
inhibitors,
tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat
and its orally
bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat
(NSC 683551)
BMS-279251 , BAY 12-9566, TAA211 , M1V1I270B or AAJ996.
[00273] The term "compounds used in the treatment of hematologic malignancies"
as used
herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors,
which are compounds
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targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase
receptors (Flt-3R);
interferon, 1-0-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK
inhibitors, which are
compounds which target, decrease or inhibit anaplastic lymphoma kinase.
[00274] Compounds which target, decrease or inhibit the activity of FMS-like
tyrosine kinase
receptors (Flt-3R) are especially compounds, proteins or antibodies which
inhibit members of the
Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine
derivative, SU11248
and MLN518.
[00275] The term "HSP90 inhibitors" as used herein includes, but is not
limited to, compounds
targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90;
degrading, targeting,
decreasing or inhibiting the HSP90 client proteins via the ubiquitin
proteosome pathway.
Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of
HSP90 are
especially compounds, proteins or antibodies which inhibit the ATPase activity
of HSP90, such as
17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative;
other
geldanamycin related compounds; radicicol and HDAC inhibitors.
[00276] The term "antiproliferative antibodies" as used herein includes,
but is not limited to,
trastuzumab (HerceptinTm), Trastuzumab-DM1, erbitux, bevacizumab (AvastinTm),
rituximab
(Rituxanc)), PR064553 (anti-CD40) and 2C4 Antibody. By antibodies is meant
intact monoclonal
antibodies, polyclonal antibodies, multispecific antibodies formed from at
least 2 intact antibodies,
and antibodies fragments so long as they exhibit the desired biological
activity.
[00277] For the treatment of acute myeloid leukemia (AML), compounds of the
current
invention can be used in combination with standard leukemia therapies,
especially in combination
with therapies used for the treatment of AML. In particular, compounds of the
current invention
can be administered in combination with, for example, farnesyl transferase
inhibitors and/or other
drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-
C, VP-16,
Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
[00278] Other anti-leukemic compounds include, for example, Ara-C, a
pyrimidine analog,
which is the f-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine.
Also included is
the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine
phosphate.
Compounds which target, decrease or inhibit activity of histone deacetylase
(HDAC) inhibitors
such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the
activity of the
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enzymes known as histone deacetylases. Specific HDAC inhibitors include M5275,
SAHA,
FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US
6,552,065 including,
but not limited to, N-hydroxy-344-[[[2-(2-methy1-1H-indo1-3-y1)-ethyl]-
amino]methyl]pheny1]-
2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-
3-[4-[(2-
hydroxyethyl) 2-(1H-indo1-3 -yl)ethyl] -amino]methyl]phenyl] -2E-2-
propenami de, or a
pharmaceutically acceptable salt thereof, especially the lactate salt.
Somatostatin receptor
antagonists as used herein refer to compounds which target, treat or inhibit
the somatostatin
receptor such as octreotide, and 50M230. Tumor cell damaging approaches refer
to approaches
such as ionizing radiation. The term "ionizing radiation" referred to above
and hereinafter means
ionizing radiation that occurs as either electromagnetic rays (such as X-rays
and gamma rays) or
particles (such as alpha and beta particles). Ionizing radiation is provided
in, but not limited to,
radiation therapy and is known in the art. See Hellman, Principles of
Radiation Therapy, Cancer,
in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol.
1 , pp. 248-275 (1993).
[00279] Also included are EDG binders and ribonucleotide reductase inhibitors.
The term
"EDG binders" as used herein refers to a class of immunosuppressants that
modulates lymphocyte
recirculation, such as FTY720. The term "ribonucleotide reductase inhibitors"
refers to pyrimidine
or purine nucleoside analogs including, but not limited to, fludarabine and/or
cytosine arabinoside
(ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine
(especially in combination
with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase
inhibitors are especially
hydroxyurea or 2-hydroxy-1H-isoindole-1 ,3 -di on e derivatives.
[00280] Also included are in particular those compounds, proteins or
monoclonal antibodies of
VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a
pharmaceutically
acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine
succinate;
AngiostatinTM; EndostatinTM; anthranilic acid amides; ZD4190; ZD6474; 5U5416;
5U6668;
bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as
rhuMAb and
RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors,
VEGFR-2 IgGI
antibody, Angiozyme (RPI 4610) and B evacizumab (AvastinTm).
[00281] Photodynamic therapy as used herein refers to therapy which uses
certain chemicals
known as photosensitizing compounds to treat or prevent cancers. Examples of
photodynamic
therapy include treatment with compounds, such as VisudyneTM and porfimer
sodium.
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[00282] Angiostatic steroids as used herein refers to compounds which block or
inhibit
angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-
epihydrocotisol,
cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone,
testosterone,
estrone and dexamethasone.
[00283] Implants containing corticosteroids refers to compounds, such as
fluocinolone and
dexamethasone.
[00284] Other chemotherapeutic compounds include, but are not limited to,
plant alkaloids,
hormonal compounds and antagonists; biological response modifiers, preferably
lymphokines or
interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA
or siRNA; or
miscellaneous compounds or compounds with other or unknown mechanism of
action.
[00285] The compounds of the invention are also useful as co-therapeutic
compounds for use
in combination with other drug substances such as anti-inflammatory,
bronchodilatory or
antihistamine drug substances, particularly in the treatment of obstructive or
inflammatory airways
diseases such as those mentioned hereinbefore, for example as potentiators of
therapeutic activity
of such drugs or as a means of reducing required dosaging or potential side
effects of such drugs.
A compound of the invention may be mixed with the other drug substance in a
fixed
pharmaceutical composition or it may be administered separately, before,
simultaneously with or
after the other drug substance. Accordingly the invention includes a
combination of a compound
of the invention as hereinbefore described with an anti-inflammatory,
bronchodilatory,
antihistamine or anti-tussive drug substance, said compound of the invention
and said drug
substance being in the same or different pharmaceutical composition.
[00286] Suitable anti-inflammatory drugs include steroids, in particular
glucocorticosteroids
such as budesonide, beclamethasone dipropionate, fluticasone propionate,
ciclesonide or
mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4
antagonists such
LY293111, CG5025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4
antagonists such as montelukast and zafirlukast; PDE4 inhibitors such
cilomilast (Ariflog
GlaxoSmithKline), Roflumilast (Byk Gulden),V-11294A (Napp), BAY19-8004
(Bayer), SCH-
351591 (Schering- Plough), Arofylline (Almirall Prodesfarma), PD189659 /
PD168787 (Parke-
Davis), AWD-12- 281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004
(Celgene),
VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a
agonists;
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A2b antagonists; and beta-2 adrenoceptor agonists such as albuterol
(salbutamol), metaproterenol,
terbutaline, salmeterol fenoterol, procaterol, and especially, formoterol and
pharmaceutically
acceptable salts thereof Suitable bronchodilatory drugs include
anticholinergic or antimuscarinic
compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium
salts and CHF
4226 (Chiesi), and glycopyrrolate.
[00287] Suitable antihistamine drug sub stances include cetirizine
hydrochloride,
acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine,
diphenhydramine
and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine,
epinastine,
mizolastine and tefenadine.
[00288] Other useful combinations of compounds of the invention with anti-
inflammatory
drugs are those with antagonists of chemokine receptors, e.g. CCR-1 , CCR-2,
CCR-3, CCR-4,
CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCRI , CXCR2, CXCR3, CXCR4,
CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-
351125, SCH-
55700 and SCH-D, and Takeda antagonists such as N4[4-[[[6,7-dihydro-2-(4-
methylpheny1)-5H-
benzo-cyclohepten-8-yl] carbonyl] amino] phenyl] -methyl]tetrahydro-N,N-
dimethy1-2H-pyran-4-
aminium chloride (TAK-770).
[00289] In some embodiments, one or more other therapeutic agent is a Poly ADP
ribose
polymerase (PARP) inhibitor. In some embodiments, a PARP inhibitor is selected
from olaparib
(Lynparzag, AstraZeneca); rucaparib (Rubracag, Clovis Oncology); niraparib
(Zejulag, Tesaro);
talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib
(ABT-888,
AbbVie); and BGB-290 (BeiGene, Inc.).
[00290] The term "Bc1-2 inhibitor" as used herein includes, but is not limited
to compounds
having inhibitory activity against B-cell lymphoma 2 protein (Bc1-2),
including but not limited to
ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bc1-2 inhibitors,
curcumin (and
analogs thereof), dual B c1-2/B cl-xL inhibitors (Infinity Pharm aceuti c al
s/Novarti s
Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof see
W02008118802),
navitoclax (and analogs thereof, see U573 90799), NH-1 (Shenayng
Pharmaceutical University),
obatoclax (and analogs thereof, see W02004106328), S-001 (Gloria
Pharmaceuticals), TW series
compounds (Univ. of Michigan), and venetoclax. In some embodiments the Bc1-2
inhibitor is a
small molecule therapeutic. In some embodiments the Bc1-2 inhibitor is a
peptidomimetic.
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[00291] In some embodiments, one or more other therapeutic agent is an
inhibitor of anti-
apoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used
in the present
invention include venetoclax (Venclextag, AbbVie/Genentech); and blinatumomab
(Blincytog,
Amgen). Other therapeutic agents targeting apoptotic proteins which have
undergone clinical
testing and may be used in the present invention include navitoclax (ABT-263,
Abbott), a BCL-2
inhibitor (NCT02079740).
[00292] The structure of the active compounds identified by code numbers,
generic or trade
names may be taken from the actual edition of the standard compendium "The
Merck Index" or
from databases, e.g. Patents International (e.g. IN/IS World Publications).
[00293] A compound of the current invention may also be used in combination
with known
therapeutic processes, for example, the administration of hormones or
radiation. In certain
embodiments, a provided compound is used as a radiosensitizer, especially for
the treatment of
tumors which exhibit poor sensitivity to radiotherapy.
[00294] A compound of the current invention can be administered alone or in
combination with
one or more other therapeutic compounds, possible combination therapy taking
the form of fixed
combinations or the administration of a compound of the invention and one or
more other
therapeutic compounds being staggered or given independently of one another,
or the combined
administration of fixed combinations and one or more other therapeutic
compounds. A compound
of the current invention can besides or in addition be administered especially
for tumor therapy in
combination with chemotherapy, radiotherapy, immunotherapy, phototherapy,
surgical
intervention, or a combination of these. Long-term therapy is equally possible
as is adjuvant
therapy in the context of other treatment strategies, as described above.
Other possible treatments
are therapy to maintain the patient's status after tumor regression, or even
chemopreventive
therapy, for example in patients at risk.
[00295] Those additional agents may be administered separately from an
inventive compound-
containing composition, as part of a multiple dosage regimen. Alternatively,
those agents may be
part of a single dosage form, mixed together with a compound of this invention
in a single
composition. If administered as part of a multiple dosage regime, the two
active agents may be
submitted simultaneously, sequentially or within a period of time from one
another normally
within five hours from one another.
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[00296] As used herein, the term "combination," "combined," and related terms
refers to the
simultaneous or sequential administration of therapeutic agents in accordance
with this invention.
For example, a compound of the present invention may be administered with
another therapeutic
agent simultaneously or sequentially in separate unit dosage forms or together
in a single unit
dosage form. Accordingly, the present invention provides a single unit dosage
form comprising a
compound of the current invention, an additional therapeutic agent, and a
pharmaceutically
acceptable carrier, adjuvant, or vehicle.
[00297] The amount of both an inventive compound and additional therapeutic
agent (in those
compositions which comprise an additional therapeutic agent as described
above) that may be
combined with the carrier materials to produce a single dosage form will vary
depending upon the
host treated and the particular mode of administration. Preferably,
compositions of this invention
should be formulated so that a dosage of between 0.01 - 100 mg/kg body
weight/day of an
inventive compound can be administered.
[00298] In those compositions which comprise an additional therapeutic agent,
that additional
therapeutic agent and the compound of this invention may act synergistically.
Therefore, the
amount of additional therapeutic agent in such compositions will be less than
that required in a
monotherapy utilizing only that therapeutic agent. In such compositions a
dosage of between 0.01
¨ 1,000 g/kg body weight/day of the additional therapeutic agent can be
administered.
[00299] The amount of additional therapeutic agent present in the compositions
of this
invention will be no more than the amount that would normally be administered
in a composition
comprising that therapeutic agent as the only active agent. Preferably the
amount of additional
therapeutic agent in the presently disclosed compositions will range from
about 50% to 100% of
the amount normally present in a composition comprising that agent as the only
therapeutically
active agent.
[00300] The compounds of this invention, or pharmaceutical compositions
thereof, may also be
incorporated into compositions for coating an implantable medical device, such
as prostheses,
artificial valves, vascular grafts, stents and catheters. Vascular stents, for
example, have been used
to overcome restenosis (re-narrowing of the vessel wall after injury).
However, patients using
stents or other implantable devices risk clot formation or platelet
activation. These unwanted
effects may be prevented or mitigated by pre-coating the device with a
pharmaceutically
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acceptable composition comprising a kinase inhibitor. Implantable devices
coated with a
compound of this invention are another embodiment of the present invention.
Exemplary Immuno-Oncology agents
[00301] In some embodiments, one or more other therapeutic agent is an immuno-
oncology
agent. As used herein, the term "an immuno-oncology agent" refers to an agent
which is effective
to enhance, stimulate, and/or up-regulate immune responses in a subject. In
some embodiments,
the administration of an immuno-oncology agent with a compound of the
invention has a synergic
effect in treating a cancer.
[00302] An immuno-oncology agent can be, for example, a small molecule drug,
an antibody,
or a biologic or small molecule. Examples of biologic immuno-oncology agents
include, but are
not limited to, cancer vaccines, antibodies, and cytokines. In some
embodiments, an antibody is a
monoclonal antibody. In some embodiments, a monoclonal antibody is humanized
or human.
[00303] In some embodiments, an immuno-oncology agent is (i) an agonist of a
stimulatory
(including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory
(including a co-
inhibitory) signal on T cells, both of which result in amplifying antigen-
specific T cell responses.
[00304] Certain of the stimulatory and inhibitory molecules are members of the
immunoglobulin super family (IgSF). One important family of membrane-bound
ligands that bind
to co-stimulatory or co-inhibitory receptors is the B7 family, which includes
B7-1, B7-2, B7-H1
(PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-
H6.
Another family of membrane bound ligands that bind to co-stimulatory or co-
inhibitory receptors
is the TNF family of molecules that bind to cognate TNF receptor family
members, which includes
CD40 and CD4OL, OX-40, OX-40L, CD70, CD27L, CD30, CD3OL, 4-1BBL, CD137 (4-
1BB),
TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL,
TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTOR, LIGHT,
DcR3, HVEM, VEGUTL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,
Lymphotoxin a/TNFP, TNFR2, TNFa, LTPR, Lymphotoxin al 02, FAS, FASL, RELT,
DR6,
TROY, NGFR.
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[00305] In some embodiments, an immuno-oncology agent is a cytokine that
inhibits T cell
activation (e.g., IL-6, IL-10, TGF-0, VEGF, and other immunosuppressive
cytokines) or a cytokine
that stimulates T cell activation, for stimulating an immune response.
[00306] In some embodiments, a combination of a compound of the invention and
an immuno-
oncology agent can stimulate T cell responses. In some embodiments, an immuno-
oncology agent
is: (i) an antagonist of a protein that inhibits T cell activation (e.g.,
immune checkpoint inhibitors)
such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA,
CD69,
Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1,
and TIM-
4; or (ii) an agonist of a protein that stimulates T cell activation such as
B7-1, B7-2, CD28, 4-1BB
(CD137), 4-1BBL, ICOS, ICOS-L, 0X40, OX4OL, GITR, GITRL, CD70, CD27, CD40, DR3
and
CD28H.
[00307] In some embodiments, an immuno-oncology agent is an antagonist of
inhibitory
receptors on NK cells or an agonists of activating receptors on NK cells. In
some embodiments,
an immuno-oncology agent is an antagonists of KIR, such as lirilumab.
[00308] In some embodiments, an immuno-oncology agent is an agent that
inhibits or depletes
macrophages or monocytes, including but not limited to CSF-1R antagonists such
as CSF-1R
antagonist antibodies including RG7155 (W011/70024, W011/107553, W011/131407,
W013/87699, W013/119716, W013/132044) or FPA-008 (W011/140249; W013169264;
W014/036357).
[00309] In some embodiments, an immuno-oncology agent is selected from
agonistic agents
that ligate positive costimulatory receptors, blocking agents that attenuate
signaling through
inhibitory receptors, antagonists, and one or more agents that increase
systemically the frequency
of anti-tumor T cells, agents that overcome distinct immune suppressive
pathways within the
tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-
Ll/PD-1
interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal
antibody (e.g.,
daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes
such as DO, or
reverse/prevent T cell energy or exhaustion) and agents that trigger innate
immune activation
and/or inflammation at tumor sites.
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[00310] In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist.
In some
embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some
embodiments,
an antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.
[00311] In some embodiments, an immuno-oncology agent is a PD-1 antagonist. In
some
embodiments, a PD-1 antagonist is administered by infusion. In some
embodiments, an immuno-
oncology agent is an antibody or an antigen-binding portion thereof that binds
specifically to a
Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity. In some
embodiments, a PD-1
antagonist is an antagonistic PD-1 antibody. In some embodiments, an
antagonistic PD-1 antibody
is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514;
W02012/145493). In some embodiments, an immuno-oncology agent may be
pidilizumab (CT-
011). In some embodiments, an immuno-oncology agent is a recombinant protein
composed of
the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl,
called AMP-224.
[00312] In some embodiments, an immuno-oncology agent is a PD-Li antagonist.
In some
embodiments, a PD-Li antagonist is an antagonistic PD-Li antibody. In some
embodiments, a
PD-Li antibody is MPDL3280A (RG7446; W02010/077634), durvalumab (MEDI4736),
BMS-
936559 (W02007/005874), and MSB0010718C (W02013/79174).
[00313] In some embodiments, an immuno-oncology agent is a LAG-3 antagonist.
In some
embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody. In some
embodiments, a
LAG3 antibody is BMS-986016 (W010/19570, W014/08218), or IMP-731 or IMP-321
(W008/132601, W0009/44273).
[00314] In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)
agonist. In
some embodiments, a CD137 (4-1BB) agonist is an agonistic CD137 antibody. In
some
embodiments, a CD137 antibody is urelumab or PF-05082566 (W012/32433).
[00315] In some embodiments, an immuno-oncology agent is a GITR agonist. In
some
embodiments, a GITR agonist is an agonistic GITR antibody. In some
embodiments, a GITR
antibody is BMS-986153, BMS-986156, TRX-518 (W0006/105021, W0009/009116), or
MK-
4166 (W011/028683).
[00316] In some embodiments, an immuno-oncology agent is an indoleamine (2,3)-
dioxygenase (DO) antagonist. In some embodiments, an DO antagonist is selected
from
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epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics
Corporation);
capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003
(Pfizer);
BMS :F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme
that breaks
down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (W009/73620,
W0009/1156652,
W011/56652, W012/142237).
[00317] In some embodiments, an immuno-oncology agent is an 0X40 agonist. In
some
embodiments, an 0X40 agonist is an agonistic 0X40 antibody. In some
embodiments, an 0X40
antibody is MEDI-6383 or MEDI-6469.
[00318] In some embodiments, an immuno-oncology agent is an OX4OL antagonist.
In some
embodiments, an OX4OL antagonist is an antagonistic 0X40 antibody. In some
embodiments, an
OX4OL antagonist is RG-7888 (W006/029879).
[00319] In some embodiments, an immuno-oncology agent is a CD40 agonist. In
some
embodiments, a CD40 agonist is an agonistic CD40 antibody. In some
embodiments, an immuno-
oncology agent is a CD40 antagonist. In some embodiments, a CD40 antagonist is
an antagonistic
CD40 antibody. In some embodiments, a CD40 antibody is lucatumumab or
dacetuzumab.
[00320] In some embodiments, an immuno-oncology agent is a CD27 agonist. In
some
embodiments, a CD27 agonist is an agonistic CD27 antibody. In some
embodiments, a CD27
antibody is varlilumab.
[00321] In some embodiments, an immuno-oncology agent is MGA271 (to B7H3)
(W011/109400).
[00322] In some embodiments, an immuno-oncology agent is abagovomab,
adecatumumab,
afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab,
avelumab,
blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab,
indoximod,
inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab,
MED14736,
MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab,
pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or
tremelimumab.
[00323] In some embodiments, an immuno-oncology agent is an immunostimulatory
agent. For
example, antibodies blocking the PD-1 and PD-Li inhibitory axis can unleash
activated tumor-
reactive T cells and have been shown in clinical trials to induce durable anti-
tumor responses in
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increasing numbers of tumor histologies, including some tumor types that
conventionally have not
been considered immunotherapy sensitive. See, e.g., Okazaki, T. et al. (2013)
Nat. Immunol. 14,
1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody
nivolumab (Opdivog,
Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558), has
shown
potential to improve the overall survival in patients with RCC who had
experienced disease
progression during or after prior anti-angiogenic therapy.
[00324] In some embodiments, the immunomodulatory therapeutic specifically
induces
apoptosis of tumor cells. Approved immunomodulatory therapeutics which may be
used in the
present invention include pomalidomide (Pomalystg, Celgene); lenalidomide
(Revlimidg,
Celgene); ingenol mebutate (Picatog, LEO Pharma).
[00325] In some embodiments, an immuno-oncology agent is a cancer vaccine. In
some
embodiments, the cancer vaccine is selected from sipuleucel-T (Provengeg,
Dendreon/Valeant
Pharmaceuticals), which has been approved for treatment of asymptomatic, or
minimally
symptomatic metastatic castrate-resistant (hormone-refractory) prostate
cancer; and talimogene
laherparepvec (Imlygicg, BioVex/Amgen, previously known as T-VEC), a
genetically modified
oncolytic viral therapy approved for treatment of unresectable cutaneous,
subcutaneous and nodal
lesions in melanoma. In some embodiments, an immuno-oncology agent is selected
from an
oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,
SillaJen/formerly
Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus
engineered to
express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma
(NCT00429312);
pelareorep (Reolysing, Oncolytics Biotech), a variant of respiratory enteric
orphan virus
(reovirus) which does not replicate in cells that are not RAS-activated, in
numerous cancers,
including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head
and neck
squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322);
and non-
small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348,
PsiOxus, formerly
known as ColoAd1), an adenovirus engineered to express a full length CD80 and
an antibody
fragment specific for the T-cell receptor CD3 protein, in ovarian cancer
(NCT02028117);
metastatic or advanced epithelial tumors such as in colorectal cancer, bladder
cancer, head and
neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-
102
(Targovax/formerly Oncos), an adenovirus engineered to express GM-C SF, in
melanoma
(NCT03003676); and peritoneal disease, colorectal cancer or ovarian cancer
(NCT02963831); GL-
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ONC1 (GLV-1h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered to
express beta-
galactosidase (beta-gal)/beta-glucoronidase or beta-gal/human sodium iodide
symporter (hNIS),
respectively, were studied in peritoneal carcinomatosis (NCT01443260);
fallopian tube cancer,
ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus
engineered to express
GM-C SF, in bladder cancer (NCT02365818).
[00326] In some embodiments, an immuno-oncology agent is selected from JX-929
(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-
deficient vaccinia
virus engineered to express cytosine deaminase, which is able to convert the
prodrug 5-
fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TGO2
(Targovax/formerly Oncos),
peptide-based immunotherapy agents targeted for difficult-to-treat RAS
mutations; and TILT-123
(TILT Biotherapeutics), an engineered adenovirus designated: Ad5/3-E2F-de1ta24-
hTNFa-IRES-
hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV)
engineered to express
the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can
be further
engineered to express antigens designed to raise an antigen-specific CD8+ T
cell response.
[00327] In some embodiments, an immuno-oncology agent is a T-cell engineered
to express a
chimeric antigen receptor, or CAR. The T-cells engineered to express such
chimeric antigen
receptor are referred to as a CAR-T cells.
[00328] CARs have been constructed that consist of binding domains, which may
be derived
from natural ligands, single chain variable fragments (scFv) derived from
monoclonal antibodies
specific for cell-surface antigens, fused to endodomains that are the
functional end of the T-cell
receptor (TCR), such as the CD3-zeta signaling domain from TCRs, which is
capable of generating
an activation signal in T lymphocytes. Upon antigen binding, such CARs link to
endogenous
signaling pathways in the effector cell and generate activating signals
similar to those initiated by
the TCR complex.
[00329] For example, in some embodiments the CAR-T cell is one of those
described in U.S.
Patent 8,906,682 (June; hereby incorporated by reference in its entirety),
which discloses CAR-T
cells engineered to comprise an extracellular domain having an antigen binding
domain (such as a
domain that binds to CD19), fused to an intracellular signaling domain of the
T cell antigen
receptor complex zeta chain (such as CD3 zeta). When expressed in the T cell,
the CAR is able to
redirect antigen recognition based on the antigen binding specificity. In the
case of CD19, the
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antigen is expressed on malignant B cells. Over 200 clinical trials are
currently in progress
employing CAR-T in a wide range of
indications.
[http s ://clini caltri al s . gov/ct2/re sults?term=chim eri c+anti
gen+receptors&p g=1] .
[00330] In some embodiments, an immunostimulatory agent is an activator of
retinoic acid
receptor-related orphan receptor y (RORyt). RORyt is a transcription factor
with key roles in the
differentiation and maintenance of Type 17 effector subsets of CD4+ (Th17) and
CD8+ (Tc17) T
cells, as well as the differentiation of IL-17 expressing innate immune cell
subpopulations such as
NK cells. In some embodiments, an activator of RORyt is LYC-55716 (Lycera),
which is currently
being evaluated in clinical trials for the treatment of solid tumors
(NCT02929862).
[00331] In some embodiments, an immunostimulatory agent is an agonist or
activator of a toll-
like receptor (TLR). Suitable activators of TLRs include an agonist or
activator of TLR9 such as
SD-101 (Dynavax). SD-101 is an immunostimulatory CpG which is being studied
for B-cell,
follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8
which may be
used in the present invention include motolimod (VTX-2337, VentiRx
Pharmaceuticals) which is
being studied for squamous cell cancer of the head and neck (NCT02124850) and
ovarian cancer
(NCT02431559).
[00332] Other immuno-oncology agents that may be used in the present invention
include
urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal
antibody; varlilumab
(CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178
(Bristol-
Myers Squibb), an anti-0X40 monoclonal antibody; lirilumab (IPH2102/BMS-
986015, Innate
Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab
(IPH2201,
Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab
(GS-5745,
Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR
monoclonal
antibody.
[00333] In some embodiments, an immunostimulatory agent is selected from
elotuzumab,
mifamurtide, an agonist or activator of a toll-like receptor, and an activator
of RORyt.
[00334] In some embodiments, an immunostimulatory therapeutic is recombinant
human
interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy
for melanoma and renal
cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453). In
some
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embodiments, an immunostimulatory agent is recombinant human interleukin 12
(rhIL-12). In
some embodiments, an IL-15 based immunotherapeutic is heterodimeric IL-15
(hetIL-15,
Novartis/Admune), a fusion complex composed of a synthetic form of endogenous
IL-15
complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain
(IL15:sIL-15RA),
which has been tested in Phase 1 clinical trials for melanoma, renal cell
carcinoma, non-small cell
lung cancer and head and neck squamous cell carcinoma (NCT02452268). In some
embodiments,
a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.),
NCT02544724,
or NCT02542124.
[00335] In some embodiments, an immuno-oncology agent is selected from those
described in
Jerry L. Adams et al., "Big opportunities for small molecules in immuno-
oncology," Cancer
Therapy 2015, Vol. 14, pages 603-622, the content of which is incorporated
herein by reference in
its entirety. In some embodiments, an immuno-oncology agent is selected from
the examples
described in Table 1 of Jerry L. Adams et al. In some embodiments, an immuno-
oncology agent
is a small molecule targeting an immuno-oncology target selected from those
listed in Table 2 of
Jerry L. Adams et al. In some embodiments, an immuno-oncology agent is a small
molecule agent
selected from those listed in Table 2 of Jerry L. Adams et al.
[00336] In some embodiments, an immuno-oncology agent is selected from the
small molecule
immuno-oncology agents described in Peter L. Toogood, "Small molecule immuno-
oncology
therapeutic agents," Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28,
pages 319-329, the
content of which is incorporated herein by refenrece in its entirety. In some
embodiments, an
immuno-oncology agent is an agent targeting the pathways as described in Peter
L. Toogood.
[00337] In some embodiments, an immuno-oncology agent is selected from those
described in
Sandra L. Ross et al., "Bispecific T cell engager (BiTE ) antibody constructs
can mediate
bystander tumor cell killing", PLoS ONE 12(8): e0183390, the conten of which
is incorporated
herein by reference in its entirety. In some embodiments, an immuno-oncology
agent is a
bispecific T cell engager (BiTEg) antibody construct. In some embodimens, a
bispecific T cell
engager (BiTEg) antibody construct is a CD19/CD3 bispecific antibody
construct. In some
embodimens, a bispecific T cell engager (BiTEg) antibody construct is an
EGFR/CD3 bispecific
antibody construct. In some embodimens, a bispecific T cell engager (BiTEg)
antibody construct
activates T cells. In some embodimens, a bispecific T cell engager (BiTEg)
antibody construct
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activates T cells, which release cytokines inducing upregulation of
intercellular adhesion molecule
1 (ICAM-1) and FAS on bystander cells. In some embodimens, a bispecific T cell
engager
(BiTEg) antibody construct activates T cells which result in induced bystander
cell lysis. In some
embodiments, the bystander cells are in solid tumors. In some embodiments, the
bystander cells
being lysed are in proximity to the BiTEg-acticvated T cells. In some
embodiment, the bystander
cells comprises tumor-associated antigen (TAA) negatgive cancer cells. In some
embodiment, the
bystander cells comprise EGFR-negative cancer cells. In some embodiments, an
immuno-
oncology agent is an antibody which blocks the PD-L 1/PD1 axis and/or CTLA4.
In some
embodiments, an immuno-oncology agent is an ex-vivo expanded tumor-
infiltrating T cell. In
some embodiments, an immuno-oncology agent is a bispecific antibody construct
or chimeric
antigen receptors (CARs) that directly connect T cells with tumor-associated
surface antigens
(TAAs).
Exemplary Immune Checkpoint Inhibitors
[00338] In some embodiments, an immuno-oncology agent is an immune checkpoint
inhibitor
as described herein.
[00339] The term "checkpoint inhibitor" as used herein relates to agents
useful in preventing
cancer cells from avoiding the immune system of the patient. One of the major
mechanisms of
anti-tumor immunity subversion is known as "T-cell exhaustion," which results
from chronic
exposure to antigens that has led to up-regulation of inhibitory receptors.
These inhibitory
receptors serve as immune checkpoints in order to prevent uncontrolled immune
reactions.
[00340] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte
antigen 4 (CTLA-4,
B and T Lymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin
domain-3
(Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often
referred to as a
checkpoint regulators. They act as molecular "gatekeepers" that allow
extracellular information
to dictate whether cell cycle progression and other intracellular signaling
processes should
proceed.
[00341] In some embodiments, an immune checkpoint inhibitor is an antibody to
PD-1. PD-1
binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor
from binding to the
inhibitory ligand PDL-1, thus overriding the ability of tumors to suppress the
host anti-tumor
immune response.
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[00342] In one aspect, the checkpoint inhibitor is a biologic therapeutic
or a small molecule. In
another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized
antibody, a fully
human antibody, a fusion protein or a combination thereof In a further aspect,
the checkpoint
inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1,
B7-H3, B7-H4,
BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2,
A2aR, B-7 family ligands or a combination thereof. In an additional aspect,
the checkpoint
inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-
4, PDL1, PDL2, PD1,
B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-
15049,
CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof In an aspect,
the checkpoint
inhibitor is an immunostimulatory agent, a T cell growth factor, an
interleukin, an antibody, a
vaccine or a combination thereof In a further aspect, the interleukin is IL-7
or IL-15. In a specific
aspect, the interleukin is glycosylated IL-7. In an additional aspect, the
vaccine is a dendritic cell
(DC) vaccine.
[00343] Checkpoint inhibitors include any agent that blocks or inhibits in
a statistically
significant manner, the inhibitory pathways of the immune system. Such
inhibitors may include
small molecule inhibitors or may include antibodies, or antigen binding
fragments thereof, that
bind to and block or inhibit immune checkpoint receptors or antibodies that
bind to and block or
inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules
that may be
targeted for blocking or inhibition include, but are not limited to, CTLA-4,
PDL1, PDL2, PD1,
B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the
CD2
family of molecules and is expressed on all NK, y6, and memory CD8+ (c43) T
cells), CD160 (also
referred to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-
7 family
ligands. B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-
DC, B7-H1, B7-H2,
B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include
antibodies, or antigen
binding fragments thereof, other binding proteins, biologic therapeutics, or
small molecules, that
bind to and block or inhibit the activity of one or more of CTLA-4, PDL1,
PDL2, PD1, BTLA,
HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative
immune
checkpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody), anti-
0X40, PD-Ll
monoclonal Antibody (Anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab
(anti-PD1
antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-
PDL1
antibody), BMS- 936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody),
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MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpoint
inhibitor).
Checkpoint protein ligands include, but are not limited to PD-L1, PD-L2, B7-
H3, B7-H4, CD28,
CD86 and TIM-3.
[00344] In certain embodiments, the immune checkpoint inhibitor is selected
from a PD-1
antagonist, a PD-Li antagonist, and a CTLA-4 antagonist. In some embodiments,
the checkpoint
inhibitor is selected from the group consisting of nivolumab (Opdivog),
ipilimumab (Yervoy ),
and pembrolizumab (Keytrudag). In some embodiments, the checkpoint inhibitor
is selected from
nivolumab (anti-PD-1 antibody, Opdivo , Bristol-Myers Squibb); pembrolizumab
(anti-PD-1
antibody, Keytruda , Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy ,
Bristol-Myers
Squibb); durvalumab (anti-PD-Li antibody, Imfinzi , AstraZeneca); and
atezolizumab (anti-PD-
Li antibody, Tecentriq , Genentech).
[00345] In some embodiments, the checkpoint inhibitor is selected from the
group consisting
of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-
224,
MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101,
pembrolizumab (Keytrudag), and tremelimumab.
[00346] In some embodiments, an immune checkpoint inhibitor is REGN2810
(Regeneron), an
anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636);
NSCLC
(NC T03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma
(NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known
as CT-
011, an antibody that binds to PD-1, in clinical trials for diffuse large B-
cell lymphoma and
multiple myeloma; avelumab (Bavencio , Pfizer/Merck KGaA), also known as
MSB0010718C),
a fully human IgG1 anti-PD-Li antibody, in clinical trials for non-small cell
lung cancer, Merkel
cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer,
bladder cancer, head and
neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody
that binds to PD-1,
in clinical trials for non-small cell lung cancer, melanoma, triple negative
breast cancer and
advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is
a fully human
monoclonal antibody against CTLA-4 that has been in studied in clinical trials
for a number of
indications, including: mesothelioma, colorectal cancer, kidney cancer, breast
cancer, lung cancer
and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic
cancer, germ cell
cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma,
prostate cancer,
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endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell
lymphoma, ovarian
cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial
cancer, fallopian tube
cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma.
AGEN-1884
(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical
trials for advanced
solid tumors (NCT02694822).
[00347] In some embodiments, a checkpoint inhibitor is an inhibitor of T-cell
immunoglobulin
mucin containing protein-3 (TIM-3). TIM-3 inhibitors that may be used in the
present invention
include TSR-022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3
antibody which
is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an
anti-TIM-3
antibody which is being studied in solid tumors (NCT03099109). MBG453
(Novartis) is an anti-
TIM-3 antibody which is being studied in advanced malignancies (NCT02608268).
[00348] In some embodiments, a checkpoint inhibitor is an inhibitor of T cell
immunoreceptor
with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and
NK cells. TIGIT
inhibitors that may be used in the present invention include BMS-986207
(Bristol-Myers Squibb),
an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and
anti-TIGIT
monoclonal antibody (NCT03119428).
[00349] In some embodiments, a checkpoint inhibitor is an inhibitor of
Lymphocyte Activation
Gene-3 (LAG-3). LAG-3 inhibitors that may be used in the present invention
include BMS-
986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-
3
antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981).
REGN3767
(Regeneron), is also an anti-LAG-3 antibody, and is being studied in
malignancies
(NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusion protein, being
studied in
melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast
cancer
(NCT00349934).
[00350] Checkpoint inhibitors that may be used in the present invention
include 0X40 agonists.
0X40 agonists that are being studied in clinical trials include PF-04518600/PF-
8600 (Pfizer), an
agonistic anti-0X40 antibody, in metastatic kidney cancer (NCT03092856) and
advanced cancers
and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic
anti-0X40
antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562
(Medimmune/AstraZeneca), an
agonistic anti-0X40 antibody, in advanced solid tumors (NCT02318394 and
NCT02705482);
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MEDI6469, an agonistic anti-0X40 antibody (Medimmune/AstraZeneca), in patients
with
colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck
cancer
(NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178
(Bristol-
Myers Squibb) an agonistic anti-0X40 antibody, in advanced cancers
(NCT02737475).
[00351] Checkpoint inhibitors that may be used in the present invention
include CD137 (also
called 4-1BB) agonists. CD137 agonists that are being studied in clinical
trials include
utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse
large B-cell
lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and
NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-
CD137
antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and
gliosarcoma
(NC TO2658981).
[00352] Checkpoint inhibitors that may be used in the present invention
include CD27 agonists.
CD27 agonists that are being studied in clinical trials include varlilumab
(CDX-1127, Celldex
Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck
cancer, ovarian
carcinoma, colorectal cancer, renal cell cancer, and glioblastoma
(NCT02335918); lymphomas
(NCT01460134); and glioma and astrocytoma (NCT02924038).
[00353] Checkpoint inhibitors that may be used in the present invention
include glucocorticoid-
induced tumor necrosis factor receptor (GITR) agonists. GITR agonists that are
being studied in
clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR
antibody, in malignant
melanoma and other malignant solid tumors (NCT01239134 and NCT02628574);
GWN323
(Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT
02740270);
INCAGN01876 (Incyte/Agenus), an agonistic anti-GITR antibody, in advanced
cancers
(NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR
antibody, in solid
tumors (NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistic
hexameric
GITR-ligand molecule with a human IgG1 Fc domain, in advanced solid tumors
(NCT02583165).
[00354] Checkpoint inhibitors that may be used in the present invention
include inducible T-
cell co-stimulator (ICOS, also known as CD278) agonists. ICOS agonists that
are being studied
in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS
antibody, in lymphomas
(NCT02520791); G5K3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1
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(NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS
antibody, in Phase 1
(NCT02904226).
[00355] Checkpoint inhibitors that may be used in the present invention
include killer IgG-like
receptor (KIR) inhibitors. KIR inhibitors that are being studied in clinical
trials include lirilumab
(IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), an anti-KIR
antibody, in
leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple
myeloma
(NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in
myeloma
(NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR
antibody that
binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma
(NCT02593045).
[00356] Checkpoint inhibitors that may be used in the present invention
include CD47
inhibitors of interaction between CD47 and signal regulatory protein alpha
(SIRPa). CD47/SIRPa
inhibitors that are being studied in clinical trials include ALX-148 (Alexo
Therapeutics), an
antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-
mediated signaling,
in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble
recombinant
fusion protein created by linking the N-terminal CD47-binding domain of SIRPa
with the Fc
domain of human IgGl, acts by binding human CD47, and preventing it from
delivering its "do
not eat" signal to macrophages, is in clinical trials in Phase 1 (NCT02890368
and NCT02663518);
CC-90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and
Hu5F9-G4
(Forty Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782),
acute myeloid
leukemia (NCT02678338) and lymphoma (NCT02953509).
[00357] Checkpoint inhibitors that may be used in the present invention
include CD73
inhibitors. CD73 inhibitors that are being studied in clinical trials include
MEDI9447
(Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-
986179
(Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).
[00358] Checkpoint inhibitors that may be used in the present invention
include agonists of
stimulator of interferon genes protein (STING, also known as transmembrane
protein 173, or
TMEM173). Agonists of STING that are being studied in clinical trials include
MK-1454
(Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma
(NCT03010176); and ADU-
S100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic
dinucleotide, in Phase 1
(NCT02675439 and NCT03172936).
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[00359] Checkpoint inhibitors that may be used in the present invention
include CSF1R
inhibitors. CSF1R inhibitors that are being studied in clinical trials include
pexidartinib
(PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer,
pancreatic cancer,
metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell
lung cancer,
squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and
ovarian cancer
(NCT02452424); and IMC-054 (LY3022855, Lilly), an anti-CSF-1R antibody, in
pancreatic
cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911);
and
BLZ945 (4-[2((1R,2R)-2-hydroxycycl oh exyl amino)-b enzothi az ol-6-
yloxyl] -pyridine-2-
carboxylic acid methylamide, Novartis), an orally available inhibitor of
CSF1R, in advanced solid
tumors (NCT02829723).
[00360] Checkpoint inhibitors that may be used in the present invention
include NKG2A
receptor inhibitors. NKG2A receptor inhibitors that are being studied in
clinical trials include
monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck
neoplasms
(NCT02643550) and chronic lymphocytic leukemia (NCT02557516).
[00361] In some embodiments, the immune checkpoint inhibitor is selected from
nivolumab,
pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
EXEMPLIFICATION
[00362] As depicted in the Examples below, in certain exemplary embodiments,
compounds
are prepared according to the following general procedures. It will be
appreciated that, although
the general methods depict the synthesis of certain compounds of the present
invention, the
following general methods, and other methods known to one of ordinary skill in
the art, can be
applied to all compounds and subclasses and species of each of these
compounds, as described
herein.
Preparation 1: 3-(4-Methylsulfanylpyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[1,2-
a] pyridine
NNSMe
/
CF3
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[00363] NBS (165.2 mg, 0.928 mmol) was added to a solution of 2-[(E)-2-
ethoxyviny1]-4-
methylsulfanyl-pyrimidine (181.4 mg, 0.924 mmol) in 1,4-dioxane (5.5 mL) and
water (2 mL) and
the reaction mixture was stirred at ambient temperature for 15 min. 5-
(Trifluoromethyl)pyridin-2-
amine (150 mg, 0.925 mmol) was added and the reaction mixture heated at 65-75
C for 7 hours.
The mixture was cooled to ambient temperature and diluted with saturated
aqueous NaHCO3 and
extracted with DCM. The combined organic extracts were dried (MgSO4), filtered
and
concentrated in vacuo . The residue was purified by column chromatography
(silica, Et0Ac/petrol
gradient) to give 3-(4-methylsulfanylpyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[1,2-c]pyridine
(165 mg, 58%); ESV-MS m/z 311.1 (M+H).
[00364] The following compounds were prepared using a methodology similar to
the one
described in Preparation 1:
6-Chloro-3 -(4-methyl sulfanylpyrimidin-2-yl)imidazo[1,2-c]pyridine using 5-
chloropyri din-2-
amine;
6-Chloro-7-fluoro-3 -(4-methyl sulfanylpyrimidin-2-ypimidazo[1,2-c]pyridine
using 5-chloro-4-
fluoro-pyridin-2-amine;
6-Bromo-7-fluoro-3 -(4-methyl sulfanylpyrimidin-2-ypimidazo[1,2-c]pyridine
using 5-bromo-4-
fluoro-pyridin-2-amine;
6-Chloro-7-fluoro-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-c]pyridine using
5-chloro-4-
fluoropyridin-2-amine.
Preparation 2: 3-(4-Chloropyrimidin-2-y1)-6-(trifluoromethyl)imidazo11,2-
alpyridine
NyNCI
[00365] Sulfuryl chloride (174.9 tL, 2.160 mmol) was added to a solution of
3-(4-
methylsulfanylpyrimidin-2-y1)-6-(trifluoromethyl)imidazo[1,2-c]pyridine (165
mg, 0.532 mmol)
and conc. HC1 (47.1 !IL of 37 %w/w, 0.860 mmol) in MeCN (13 mL) and the
reaction mixture
stirred for 5 minutes. Cooled saturated aqueous NaHCO3 was added dropwise and
the mixture
stirred for 10 min. The resultant precipitate was isolated by filtration,
washed with water and dried
to give 3-(4-chloropyrimidin-2-y1)-6-(trifluoromethyl)imidazo[1,2-c]pyridine
(125 mg, 79%).
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[00366] The following compounds were prepared using a methodology similar to
the one
described in Preparation 2:
6-Chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-c]pyridine
using 6-chl oro-3 -(4-
methyl sulfanylpyrimidin-2-ypimidazo[1,2-c]pyridine;
6-Chloro-3-(4-chloropyrimidin-2-y1)-7-fluoro-imidazo[1,2-c]pyridine using 6-
chloro-7-fluoro-3-
(4-methyl sulfanylpyrimidin-2-yl)imidazo[1,2-c]pyridine;
6-Bromo-3-(4-chloropyrimidin-2-y1)-7-fluoro-imidazo[1,2-c]pyridine using 6-
bromo-7-fluoro-3-
(4-methyl sulfanylpyrimidin-2-yl)imidazo[1,2-c]pyridine;
6-Chloro-3-(4-chloropyrimidin-2-y1)-7-fluoro-imidazo[1,2-c]pyridine using 6-
chloro-7-fluoro-3-
(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a] pyri dine.
4-Chloro-2-{6-phenoxyimidazo[1,2-a]pyridin-3-yl}pyrimidine
4-Chloro-2-{6-methanesulfonylimidazo[1,2-a]pyridin-3-yl}pyrimidine
3 -(4-Chloropyrimidin-2-y1)-N-cyclopropylimidazo[1,2-a]pyridine-6-sulfonamide
3 -(4-Chloropyrimidin-2-ypimidazo[1,2-a]pyridine-6-sulfonamide
Preparation 3: 3-Bromo-6-(difluoromethyl)imidazo[1,2-alpyridine
NBr
CF2H
[00367]
(Diethylamino)sulfur trifluoride (528.5 tL, 4.00 mmol) was added dropwise to 3-
bromoimidazo[1,2-c]pyridine-6-carbaldehyde (450 mg, 2.00 mmol) in DCM (4.5 mL)
at 0 C.
After 2.5 hours, additional (diethylamino)sulfur trifluoride (150 tL, 1.135
mmol) was added and
the reaction stirred at room temperature for 16 hours. The crude mixture was
diluted with methanol
and purified by means of an ion exchange SCX-2 cartridge to afford 3-bromo-6-
(difluoromethyl)imidazo[1,2-c]pyridine (310 mg, 63%); ESV-MS m/z 247.0 (M+H).
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Preparation 4: 2-16-(Difluoromethyl)imidazo 11,2-al pyridin-3-yll pyrimidin-4-
ol
y -140H
CF2H
Step 1: 6-(Difluoromethyl)-3-(4-methoxypyrimidin-2-y1)imidazo11,2-al pyridine
[00368] 3-Bromo-6-(difluoromethyl)imidazo[1,2-c]pyridine (120 mg, 0.486
mmol), tributyl-
(4-methoxypyrimidin-2-yl)stannane (200 tL, 0.583 mmol) and PdC12(PPh3)2 (102.3
mg, 0.146
mmol) were combined in DMF (4 mL) and degassed with nitrogen and heated at 120
C for 16
hours. The mixture was allowed to cool, filtered and then purified by reverse
phase
chromatography (C18; MeCN/water/0.05% TFA as eluent) to afford the
trifluoroacetic acid salt
of 6-(difluoromethyl)-3-(4-methoxypyrimidin-2-yl)imidazo[1,2-c]pyridine (97
mg, 72%); ESV-
MS m/z 277.1 (M+H).
Step 2: 2-16-(Difluoromethyl)imidazo 11,2-al pyridin-3-yll pyrimidin-4-ol
[00369] Chlorotrimethylsilane (267 tL, 2.107 mmol) was added to a solution of
6-
(difluoromethyl)-3-(4-methoxypyrimidin-2-yl)imidazo[1,2-c]pyridine (97 mg,
0.351 mmol) and
NaI (315.8 mg, 2.107 mmol) in MeCN (4 mL) and the mixture was heated at 80 C
for 16 hours.
The reaction mixture was cooled to room temperature and the solvent removed
under reduced
pressure. The residue was suspended in water and washed with saturated aqueous
sodium
thiosulfate. The solid was filtered, washed with water, and dried under vacuum
to afford 246-
(difluoromethyl)imidazo[1,2-c]pyridin-3-yl]pyrimidin-4-ol (75 mg, 81%); ESV-MS
m/z 263.1
(M+H). The material was used without further purification.
Preparation 5: 3-(2-Chloropyrimidin-4-y1)-6-(trifluoromethyl)imidazo11,2-
alpyridine
N Nr 'NI CI
CF3
[00370] NBS (241 mg, 1.354 mmol) was added to a solution of 2-chloro-4-(2-
ethoxyvinyl)pyrimidine (250 mg, 1.354 mmol) in 1,4-dioxane (8 mL) / water (3
mL) and the
reaction mixture was stirred for 15 min. 5-(Trifluoromethyl)pyridin-2-amine
(220 mg, 1.357
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mmol) was added and the reaction mixture heated at 80 C for 3 hours. The
mixture was cooled to
room temperature and diluted with saturated aqueous NaHCO3 and extracted with
DCM. The
combined organic extracts were dried (MgSO4), filtered and concentrated in
vacuo. The residue
was purified by flash column chromatography (silica, Et0Ac/petrol gradient,
then Me0H/DCM
gradient) to afford 3-(2-chloropyrimidin-4-y1)-6-(trifluoromethyl)imidazo[1,2-
c]pyridine (234.5
mg, 58%) as a beige solid.; 111NMR (500 MHz, DMSO-d6) 6 10.26 (s, 1H), 8.95
(s, 1H), 8.78 (d,
1H), 8.19 (d, 1H), 8.05 (d, 1H), 7.84 (dd, 1H); 1-9F NMR (471 MHz, DMSO-d6) 6
¨60.86; ESV-
MS m/z 299.1 (M+H).
Preparation 6: N-I1(25)-Morpholin-2-yllmethyllmethanesulfonamide
0,0
MsCI =C
.0 ii) TFA
r
NH2
Step 1: tert-butyl (S)-2-(methylsulfonamidomethyl)morpholine-4-carboxylate
[00371] To a round bottom flask was added tert-butyl (2R)-2-
(aminomethyl)morpholine-4-
carboxylate (5 g, 23 mmol) and Et3N (16.1 mL, 115 mmol) followed by THF (100
mL). DCM (50
mL) was added and the mixture was cooled to 0 C. Methanesulfonyl chloride
(2.4 mL, 30.5 mmol)
was added dropwise and the mixture stirred for 0.5 hours then left at ambient
temperature for 16
hours under an atmosphere of N2. The reaction was quenched with saturated
aqueous NaHCO3
solution (100 mL) and the majority of the volatiles were removed in vacuo. The
aqueous layer was
extracted with ethyl acetate (3 x 50 mL). The combined organics were dried
over Na2SO4, filtered
and concentrated in vacuo. The residue was purified by chromatography (silica;
70 - 100% Et0Ac
/Petroleum ether gradient elution). The product fractions were combined and
concentrated in
vacuo. The residue was dried overnight under vacuum to give tert-butyl (S)-2-
(methylsulfonamidomethyl)morpholine-4-carboxylate (3.61 g, 53 %) as a white
solid; 11-1 NMR
(500 MHz, Chloroform-d) 6 4.71 - 4.59 (m, 1H), 3.98 - 3.82 (m, 2H), 3.63 -
3.49 (m, 2H), 3.38 -
3.24 (m, 1H), 3.20 - 3.11 (m, 1H), 3.04 - 2.90 (m, 4H), 2.73 (s, 1H), 1.49 (s,
9H).
Step 2: N-11(2S)-Morpholin-2-yllmethyllmethanesulfonamide
[00372] TFA (9 mL, 115 mmol) was added to a stirred solution of tert-butyl
(2S)-2-
(methanesulfonamidomethyl)morpholine-4-carboxylate (3.6 g, 12 mmol) in DCM (60
mL) and
the reaction stirred at ambient temperature for 6 hours. The solvent was
removed in vacuo and the
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residue azeotroped with DCM (x 2) and diethyl ether (x 2). The residue was
taken up in methanol
and passed through an ion-exchange cartridge, eluting with methanol
(discarded) then a 2M
methanolic ammonia solution. The filtrate was concentrated in vacuo to give N-
R2S)-morpholin-
2-yl]methyl]methanesulfonamide (2.3 g, 97%); 1-H NMR (500 MHz, Chloroform-d) 6
4.73 (s, 1H),
3.90 - 3.87 (m, 1H), 3.65 - 3.60 (m, 2H), 3.26 (dd, 1H), 3.09 (dd, 1H), 2.99
(s, 3H), 2.92 - 2.84 (m,
3H), 2.66 (dd, 1H); MS m/z: 195 (M+H).
Preparation 7: 2-(1H-Pyrazol-4-yl)morpholine
Boc
Boc
i) DMF-DMA C j HCI C
C jC
0 ii) N2H4 0 0N N
Step 1: tert-Butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate
[00373] A mixture of tert-butyl 2-(2-oxoethyl)morpholine-4-carboxylate (5.77
g, 25 mmol) and
DMF-DMA (6.7 mL, 50 mmol) in DMF (50 mL) was stirred at 80 C for 17 hours.
The reaction
mixture was cooled to ambient temperature and the solvent removed in vacuo.
The residue was
taken up in Et0H (100 mL) and hydrazine hydrate (1.3 mL, 26.5 mmol) was added
with stirring
at ambient temperature. After 3 hours, the solvent was removed in vacuo and
the residue purified
by chromatography (silica, PE/Et0Ac gradient elution), to give tert-butyl 2-
(1H-pyrazol-4-
yl)morpholine-4-carboxylate (2.35 g, 37 %) as a yellow solid. 1H NMR (500 MHz,
chloroform-d)
6 7.63 (s, 2H), 4.52 (dd, 1H), 4.12 (br s, 1H), 3.97 - 3.90 (m, 2H), 3.68 (td,
1H), 3.05 (d, 2H), 1.51
(s, 9H); MS m/z: 254.1 (M+H).
Step 2: 2-(1H-Pyrazol-4-yl)morpholine
[00374] 3M HC1 in methanol (45 mL of 3M, 135 mmol) was added to a stirred
solution of tert-
butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate (2.35 g, 9.3 mmol) in DCM
(75 mL) and the
reaction heated at reflux for 5 hours. The reaction was cooled to ambient
temperature and the
solvent removed in vacuo. The residue was dissolved in the minimum amount of
DCM/Me0H and
loaded on to an ion-exchange cartridge. The cartridge was washed with Me0H/DCM
mixtures,
which were discarded. The product was eluted by washing with 2M NH3 in
Me0H/DCM. The
solvent was removed in vacuo to give 2-(1H-pyrazol-4-yl)morpholine (1.27 g, 89
%) as an orange
solid, which was taken on to the next reaction without further purification; 1-
H NMR (500 MHz,
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chloroform-d) 6 7.60 (s, 2H), 4.56 (dd, 1H), 3.98 (ddd, 1H), 3.77 (td, 1H),
3.11 (dd, 1H), 3.00 (td,
1H), 2x.93 - 2.88 (m, 2H); MS m/z: 154.2 [M+H]
Preparation 8: 2-Methyl-6-(1H-pyrazol-4-y1)morpholine.
H2N CION
i) Br
' i) LiAIH4
i) NO2Me 0
0 N HO N ii) NaH ON N N 0 jr
ii) H2, Pd/C 'Bn ii) H2, Pd/C IBri NBn NH
[00375] To a solution of 1-benzylpyrazole-4-carbaldehyde (2 g, 10.7 mmol) and
nitromethane
(7 mL, 129 mmol) cooled in an ice bath, was added Et3N (150 L, 1.1 mmol). The
mixture was
stirred with cooling for 15 minutes, then at ambient temperature for 18 hours.
The reaction mixture
was concentrated in vacuo and the residue purified by chromatography (silica,
Et0Ac/Petroleum
ether gradient elution). The relevant fractions were combined and concentrated
in vacuo to give a
colourless oil (1 g, 37%); MS m/z: 248 (M+H)t This material was taken directly
onto the next
reaction.
[00376] A mixture of 1-(1-benzylpyrazol-4-y1)-2-nitro-ethanol (100 mg, 0.4
mmol), Pd on C,
wet, Degussa (20 mg, 0.2 mmol) in methanol (4 mL) was stirred at ambient
temperature for 18
hours under H2 at 1 atmosphere. The reaction mixture was filtered and the
filtrate concentrated in
vacuo to give a colourless gum (90 mg); MS m/z: 218 (M+H)+. This material was
taken directly
onto next the reaction.
[00377] 2-Bromopropanoyl bromide (114 mg, 0.5 mmol) was added to an ice-cold
solution of
2-amino-1-(1-benzylpyrazol-4-yl)ethanol (100 mg, 0.5 mmol) and Et3N (83 L,
0.6 mmol) in
DCM (4 mL) under N2. The reaction mixture was stirred at ambient temperature
for 1 hour. The
reaction mixture was diluted with DCM, washed with a 2M aqueous HC1 solution,
saturated
aqueous NaHCO3 solution and brine. The organic phase was dried over sodium
sulfate, filtered
and concentrated in vacuo to give a colourless oil. This material was taken up
in THF (3 mL) and
the solution cooled in an ice bath. Sodium hydride (37 mg of a 60% dispersion
in mineral oil, 0.9
mmol) was added and the resulting suspension was stirred at ambient
temperature for 2 hours. The
reaction was quenched with methanol then diluted with Et0Ac, washed with a
saturated aqueous
sodium bicarbonate solution and brine. The organic phase was dried over MgSO4,
filtered and
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concentrated in vacuo to give a pale yellow gum (100 mg), MS m/z: 272 (M+H)+,
that was taken
directly on to next reaction without purification.
[00378] A mixture of 6-(1-benzylpyrazol-4-y1)-2-methyl-morpholin-3-one (100
mg, 0.4 mmol)
and LiA1H4 (184 tL of 2M, 0.4 mmol) in THF (3 mL) was stirred at 60 C for 1
hour. The resulting
suspension was quenched with Na2SO4.10H20 pellets and stirred for 30 minutes,
then filtered. The
filtrate was concentrated in vacuo and the residue taken up in methanol (2
mL). Three drops of
concentrated HC1 and Pd on C, wet, Degussa (20 mg, 0.02 mmol) were added to
the solution. The
reaction mixture was stirred at ambient temperature under H2 at 1 atmosphere
pressure for 18
hours. The reaction mixture was poured onto an ion-exchange cartridge and
eluted with methanol
(filtrate discarded), then a 2M methanolic NH3 solution. The filtrate was
concentrated in vacuo to
give 2-methyl-6-(1H-pyrazol-4-y1)morpholine (23 mg), MS m/z: 168 (M+H)t This
material was
taken directly onto the next reaction.
Preparation 9: Imino(methyl)(piperidin-3-ylmethy1)P-sulfanone
i) 2,2,2-trifluoroacetamide
Boc Boc
i) NaSMe Ph1(0Ac)2, Rh2(0Ac) 6
MgO 0,, ,NH
9
ci ii) mCPBA
ii) K2CO3
iii) TFA
[00379] A mixture of tert-butyl 3-(chloromethyl)piperidine- 1 -carboxylate
(500 mg, 2.14
mmol), NaSMe (3 mL of 20% w/v, 8.56 mmol), KI (355 mg, 2.14 mmol) in ethanol
(10 mL) was
stirred at 80 C for 22 hours. The reaction mixture was cooled to ambient
temperature then
concentrated in vacuo. The residue was partitioned between Et0Ac and saturated
aqueous sodium
bicarbonate solution. The organic phase was washed with brine, dried (MgSO4),
filtered and
concentrated in vacuo to give the product as a pale brown oil (460 mg 88%),
that was taken on to
the next step without further purification or characterisation.
[00380] m-CPBA (324 mg, 1.88 mmol) was added to an ice cold solution of tert-
butyl 3-
(methylsulfanylmethyl)piperidine-1-carboxylate (460 mg, 1.88 mmol) in DCM (7
mL) under N2.
The reaction mixture was stirred for 20 hours, with the temperature rising to
ambient. The reaction
mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate
solution and
brine. The organic phase was dried over MgSO4, filtered and concentrated in
vacuo to give a pale
brown oil (460 mg); MS m/z: 262 (M+H)+, that was used in the next step without
further
purification or characteri sati on. tert-Butyl 3 -(methyl
sulfinylmethyl)piperi di ne-l-carb oxyl ate (5.5
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g, 21.0 mmol), 2,2,2-trifluoroacetamide (5.2 g, 46.3 mmol),
diacetoxyiodobenzene (10.2 g, 31.6
mmol) and MgO (3.39 g, 84.2 mmol) were combined in DCM (250 mL) under N2.
Rh2(0Ac)6 (0.9
g, 2.0 mmol) was added and the reaction mixture mixture stirred at room
temperature for 16 hours.
The mixture was filtered through Celite, washing with methanol and DCM. The
filtrate was
concentrated in vacuo and the residue taken up in methanol (5 mL) and
MeCN/water (3:1) (5 mL).
K2CO3 (17.4 g, 126.0 mmol) was added and the mixture stirred at 90 C for 2
hours. The mixture
was diluted with Et0Ac and washed with saturated aqueous sodium bicarbonate
solution and
brine. The organic phase was dried (Na2SO4), filtered and concentrated in
vacuo to give tert-butyl
3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (5.96 g, quantitative
yield) as an amber
oil; MS m/z: 277 (M+H)+, that was taken directly on to the next reaction.
[00381] tert-Butyl 3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate
(600 mg, 2.17
mmol) in DCM (3 mL) was treated with TFA (1.7 mL, 21.7 mmol). The mixture was
stirred at
room temperature for 16 hours. The reaction mixture was concentrated in vacuo.
The residue was
taken up in methanol and loaded on to an ion-exchange cartridge. The cartridge
was eluted
Me0H/DCM (filtrate discarded) then with methanolic ammonia. The filtrate was
concentrated in
vacuo to give imino(methyl)(piperidin-3-ylmethy1)-6-sulfanone (250 mg, 65%); 1-
E1 NMR (500
MHz, Methanol-d4) 6 3.34 - 3.24 (m, 1H), 3.19 - 3.10 (m, 2H), 3.10 - 3.07 (m,
3H), 3.05 - 2.97
(m, 1H), 2.60 (ddd, 1H), 2.52 - 2.43 (m, 1H), 2.30 - 2.18 (m, 1H), 2.08 (ddtd,
1H), 1.75 (dq, 1H),
1.61 (dtq, 1H), 1.37 (dtd, 1H).
Preparation 10: Imino(methyl)(piperidin-3-ylmethyl)P-sulfanone
Boc Boc Boc
i) NaSMe 0 2,2,2-trifluoroacetamide N TFA
NH NII II II
0Ms ii) rriCPBA Ph1(0Ac)2, Rh2(0A06 \./\.
MgO 0 0
[00382] Sodium thiomethoxide (4.06 g, 58 mmol) was added to a solution of tert-
butyl 3-
(methylsulfonyloxymethyl)piperidine-1-carboxylate (8.5 g, 29 mmol) in ethanol
(170 mL). The
mixture was stirred at ambient temperature for 6 hours then concentrated in
vacuo. The residue
was partitioned between DCM and saturated aqueous NaHCO3 solution. The organic
phase was
dried and concentrated in vacuo. The residue was purified by chromatography
(silica,
Me0H/DCM gradient elution) to give a pale yellow oil (6.9 g). This material
was dissolved in
DCM (100 mL) and the solution cooled in an ice bath. m-CPBA (6.93 g of 70%
pure w/w, 28
mmol) was added portionwise . After addition was complete the reaction mixture
was stirred for
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minutes then partitioned between DCM, saturated aqueous sodium bicarbonate
solution and
saturated aqueous sodium thiosulfate solution. The organic phase was dried and
concentrated in
vacuo. The residue was purified by chromatography (silica, DCM/Me0H gradient
elution) to give
the product as a colourless oil.
[00383]
tert-Butyl 3-((methylsulfinyl)methyl)piperidine-1-carboxylate (5.5 g, 21.0
mmol),
2,2,2-trifluoroacetamide (5.23 g, 46.3 mmol), (diacetoxyiodo)benzene (10.17 g,
31.6 mmol) and
magnesium oxide (3.39 g, 84.2 mmol) were dissolved in DCM (250 mL) and
diacetoxy(diacetoxyrhodio)rhodium (0.9 g, 2.04 mmol) was added. The mixture
was stirred at
ambient temperature overnight before being filtered through Celite and
concentrated in vacuo. The
residue was dissolved in methanol (50 mL) and water (10 mL) and K2CO3 (17.44
g, 126.2 mmol)
was added. The mixture was stirred at ambient temperature for 3 hours before
heating 50 C for 3
days. The mixture was concentrated in vacuo and the residue dissolved in
methanol (5mL) and
acetonitrile/water (3:1 mixture, 5mL). After 1.5 hours at 90 C the mixture
was cooled, diluted in
Et0Ac and washed with brine and saturated aq. NaHCO3 solution. The organic
layer was dried
(Na2SO4) and concentrated in vacuo to give tert-butyl
3 -((S-
methylsulfonimidoyl)methyl)piperidine-1-carboxylate (5.96 g) as an amber oil
which was used
without further purification.
[00384] A solution of tert-butyl 3-[(methylsulfonimidoyl)methyl]piperidine-1-
carboxylate
(600 mg, 2.17 mmol) and TFA (1.67 mL, 21.71 mmol) in DCM (3 mL) was stirred at
ambient
temperature for 16 hours before being concentrated in vacuo and the residue
passed through an
SCX-2 cartridge. The product was eluted with ammonia in methanol to give
imino(methyl)(piperidin-3-ylmethyl)-k6-sulfanone (250 mg, 65%); 111 NMR (500
MHz,
Methanol-d4) 6 3.34 - 3.24 (m, 1H), 3.19 - 3.10 (m, 2H), 3.10 - 3.07 (m, 3H),
3.05 - 2.97 (m,
1H), 2.60 (ddd, J = 12.4, 11.5, 3.1 Hz, 1H), 2.52 - 2.43 (m, 1H), 2.30 - 2.18
(m, 1H), 2.08 (ddtd,
J = 30.1, 10.9, 3.8, 1.8 Hz, 1H), 1.75 (dq, J = 13.8, 3.3 Hz, 1H), 1.61 (dtq,
J = 13.6, 11.5, 3.8 Hz,
1H), 1.37 (dtd, J = 12.8, 11.3, 3.9 Hz, 1H).
Preparation 11: 2,5-Dimethy1-3-((methylsulfinyl)methyl)piperidine
00 o o o o o 0
i) Pt02 LiBH4 I) meci mCPBA r
I 0 ,
ii) (Boc)20 0 ii) NaSMe S S
O. 0, OH
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Step!: 1-(tert-Butyl) 3-methyl 2,5-dimethylpiperidine-1,3-dicarboxylate
oo
[00385] A mixture of methyl 2,5-dimethylpyridine-3-carboxylate (2.6 g, 15.74
mmol) and Pt02
(713 mg, 3.14 mmol) in HC1 (57 mL of a 3M solution in Me0H, 171.1 mmol) was
stirred under a
balloon of H2. The reaction mixture was stirred for 16 hours at ambient
temperature before being
filtered through Celite and the filtrate concentrated in vacuo. The residue
was dissolved in THF
(27 mL) and triethylamine (6.6 mL, 47.3 mmol), DMAP (96 mg, 0.79 mmol) and di-
tert-butyl
dicarbonate (17.4 mL of a 1M solution in THF, 17.4 mmol) sequentially added.
The reaction
mixture was stirred for 16 hours, then partitioned between Et0Ac and water.
The organic layer
was separated and washed with NH4C1 solution, water (1 x), brine (1 x), then
dried (MgSO4),
filtered and concentrated in vacuo. The residue was purified by chromatography
(silica, 0-10 %
Et0Ac/Petroleum ether gradient elution) to give 1-(tert-butyl) 3-methyl 2,5-
dimethylpiperidine-
1,3-dicarboxylate (1.4 g, 33 %) as a colourless oil containing a mixture of
diastereomers; 1H NMR
(400 MHz, Methanol-d4) 6 4.80 ¨ 4.62 (m, 1H), 3.95 ¨ 3.78 (m, 1H), 3.71 (d,
3H), 2.71 (dq, 1H),
2.46 (dt, 1H), 1.89 ¨ 1.77 (m, 1H), 1.48 (q, 10H), 1.10 ¨0.92 (m, 7H).
Step 2: tert-Butyl 3-(hydroxymethyl)-2,5-dimethylpiperidine-l-carboxylate
yo
[00386] 01-tert-Butyl 03-methyl 2,5-dimethylpiperidine-1,3-dicarboxylate (1.40
g, 5.16
mmol) was dissolved in THF (42 mL) and cooled to 0 C. Lithium borohydride
(10.3 mL of a 2M
solution in THF, 20.6 mmol) was added and the reaction allowed to warm to
ambient temperature.
After 30 minutes the reaction mixture was warmed to 50 C and stirred for 16
hours. The reaction
was cooled to ambient temperature then quenched with water. The mixture was
extracted with
Et0Ac (x 3). The combined organics were dried and concentrated in vacuo to
give tert-butyl 3-
(hydroxymethyl)-2,5-dimethyl-piperidine- 1 -carboxylate (1.25 g, 100%) as a
colourless oil that
was taken directly on to the next reaction without further purification; 1-E1
NMR (400 MHz,
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Methanol-d4) 6 4.42 - 4.27 (m, 1H), 3.82 - 3.68 (m, 1H), 3.34 - 3.23 (m, 2H),
2.33 (dt, 1H), 1.91
(s, 1H), 1.82 - 1.68 (m, 1H), 1.54 - 1.37 (m, 2H), 1.35 (s, 9H), 0.95 - 0.87
(m, 3H), 0.86 - 0.76 (m,
4H).
Step 3: tert-Butyl 2,5-dimethy1-3-(((methylsulfonyl)oxy)methyl)piperidine-1-
carboxylate
o,o
N
a.
[00387] Methanesulfonyl chloride (2.77 mL, 35.7 mmol) was added to a solution
of tert-butyl
3-(hydroxymethyl)-2,5-dimethylpiperidine-1-carboxylate (5.80 g, 23.8 mmol) and
triethylamine
(6.64 mL, 47.7 mmol) in DCM (116 mL) stirring at 0 C. After 30 mins the
reaction was quenched
with saturated aq. NaHCO3, stirred for 5 mins and then the layers separated
using a phase separator
cartridge. The organic phase was evaporated in vacuo to give tert-butyl 2,5-
dimethy1-3-
(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (7.6 g) which was used
directly in the next
step without further purification.
Step 4: tert-Butyl 2,5-dimethy1-3-((methylthio)methyl)piperidine-1-carboxylate
o,c)
[00388] Sodium thiomethoxide (9.94 g, 141.8 mmol) was added to a solution of
tert-butyl 2,5-
dimethy1-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (7.6 g, 23.6
mmol) in Et0H
(100 mL), stirring at 0 C. After addition, cooling was removed and the
reaction heated at 60 C
for 16 hours. The reaction was cooled to ambient temperature, concentrated in
vacuo and purified
by column chromatography (silica, eluting with 0-12.5% Me0H in DCM gradient)
to give tert-
butyl 2,5-dimethy1-3-((methylthio)methyl)piperidine-1-carboxylate (3.4 g, 66%)
as a colourless
oil; 1H NMIt (500 MHz, Methanol-d4) 6 4.53 -4.43 (m, 1H), 3.86 (td, J= 13.3,
4.4 Hz, 1H), 2.53
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-2.31 (m, 3H), 2.10 (s, 3H), 1.91 - 1.81 (m, 1H), 1.74- 1.63 (m, 1H), 1.61 -
1.50 (m, 1H), 1.48 (s,
9H), 1.10 - 0.99 (m, 4H), 0.93 (t, J= 6.4 Hz, 3H).
Step 5: tert-Butyl 2,5-dimethy1-3-((methylsulfinyl)methyl)piperidine-1-
carboxylate
\/
0 y0
fµl 0
[00389] tert-Butyl 2,5 -dim ethyl-3 -((m ethylthi o)m ethyl)pip eri dine-l-
carb oxyl ate (2 g, 7.31
mmol) was dissolved in DCM (73 mL) and the solution cooled to 0 C. m-CPBA
(1.80 g, 7.31
mmol) was added portionwise over 5 min and the reaction stirred for a further
5 min before being
quenched by addition of saturated aqueous sodium thiosulphate (40 mL) and
stirred for 5 min
before extracting with DCM (3 x 50 mL). The combined organics were washed with
with saturated
aq. NaHCO3 (2 x 40 mL), filtered through a phase separator cartridge and
concentrated in vacuo
to give tert-butyl 2,5-dimethy1-3-((methylsulfinyl)methyl)piperidine-1-
carboxylate (2.1 g, 100%)
as a colourless oil which was used without further purification.
Step 6: 2,5-Dimethy1-3-((methylsulfinyl)methyl)piperidine
H
N 0
[00390] tert-Butyl 2,5-dim ethyl-3 -((methyl sul finyl)m ethyl)pip eri dine-
l-carb oxyl ate (2.1 g,
7.26 mmol) was dissolved in methanol (36 mL) and 4M HC1 in dioxane (9.1 mL,
36.3 mmol) was
added. The reaction was stirred for 16 hours at ambient temperature before
being concentrated in
vacuo to give 2,5-dimethy1-3-((methylsulfinyl)methyl)piperidine (1.85 g, 97%)
as a white solid;
MS m/z: 190.1 (M+H).
Preparation 12: 2-(1H-Pyrazol-4-yl)piperazine
H
CN
N N
N I H2, Pt02/,9 (
) , c . , ______________________________
HN )011 N
N'H
\NiF:
[00391] A mixture of 2-(1H-pyrazol-4-yl)pyrazine (400 mg, 2.7 mmol) , Pt02
(100 mg, 0.4
mmol) in methanol (15 mL) was shaken at ambient temperature under a 60p5i H2
pressure for 18
hours. The reaction mixture was filtered and the filtrate concentrated in
vacuo to give 2-(1H-
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pyrazol-4-yl)piperazine as a colourless oil, which was taken directly on to
the next reaction without
purification; MS m/z: 153 (M+H)t
Preparation 13: 2,5-Dimethy1-3-(1H-pyrazol-4-yDpiperazine
o-B
N
I)
Boc
FNI*- CI H ,N
ii) Pt02, H2 NH
[00392] A 3-necked flask equipped with reflux condenser and thermometer was
charged with
3-chloro-2,5-dimethyl-pyrazine (5 mL, 40 mmol), tert-butyl 4-(4,4,5,5-
tetramethy1-1,3,2-
dioxaborolan-2-yl)pyrazole- 1 -carboxylate (10 g, 34 mmol) in 1,4-dioxane (100
mL). Pd(PPh3)4 (2
g, 2 mmol), and Na2CO3 (60 mL of 2M, 100 mmol) were added and the solution was
evacuated
and backfilled with N2 (x 2). The solution was heated at 100 C and stirred
overnight. The reaction
mixture was cooled to ambient temperature and filtered, washing with diethyl
ether. The filtrate
was concentrated in vacuo and the residue purified by chromatography (silica,
0-100%
[Et0Ac+2% 2M methanolic ammonia]-Petroleum ether gradient elution). The
product fractions
were combined and concentrated in vacuo to give 2,5-dimethy1-3-(1H-pyrazol-4-
y1)pyrazine as a
white solid (4.5 g, 64%); MS m/z: 175 (M+H)t
[00393] A mixture of 2,5-dimethy1-3-(1H-pyrazol-4-yl)pyrazine (4.5 g, 26
mmol), Pt02 (1 g, 4
mmol) and HC1 (60 mL of a 3M solution in Me0H, 200 mmol) was shaken in a Parr
hydrogenator
for 24 hours under a pressure of 60p5i H2. The reaction mixture was filtered
and the filtrate
concentrated in vacuo to give the product 2,5-dimethy1-3-(1H-pyrazol-4-
yl)piperazine as an off-
white solid (4.0 g, 61%); MS m/z: 181 (M+H)t This material was used in the
next reaction
assuming the dihydrochloride salt was isolated.
[00394] The following compounds were prepared using a methodology similar to
the one
described in Preparation 213:
2-Methy1-6-(1H-pyrazol-4-y1)piperazine;
3 -(1H-Imi dazol-4-y1)-2, 5-dimethylpiperazine.
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Preparation 14: Dimethyb(5-methylpiperidin-3-yl)imino-)P
0=S
0 /
i) 'S. 0=S
Br / 'NH Pd(OH)2, H2 gi
ii) BnBr
iii) NaBH4
Step 1: Dimethyb(5-methyl-pyridin-3-yl)imino)P-sulfanone
[00395]
3-Bromo-5-methyl-pyridine (250 g, 1.439 mol), iminodimethyl-k6-sulfane (142.6
g,
1.454 mol), Xantphos (24.976 g, 43.16 mmol), K2CO3 (218.8 g, 1.583 mol) and
tris(benzylideneacetone)dipalladium(0) (19.76 g, 21.58 mmol) were suspended in
1,4-dioxane (2.4
L). The reaction mixture was degassed (vacuum/nitrogen 3 cycles) and stirred
under reflux at 125
C for 16 hours. The reaction mixture was allowed to cool to ambient
temperature then filtered
through Celite washing with Et0Ac. The oil was diluted with a little MTBE
(just enough to see
hint of precipitation; -150m1), seeded with a few crystals of an authentic
sample and stirred at
ambient temperature for 2 hours. The solid was filtered and washed with a
minimum of MTBE to
give a light pink solid which was dried in the oven at 30 C in vacuo to give
the desired product
(105.9 g, 40%). The mother liquors were concentrated in vacuo to give 247.4g
of a dark brown
oil. 247.4g of crude mixture was purified on column column chromatography (3
kg silica column;
product adsorbed onto 350 g silica pad; 0 to 10% Me0H in Et0Ac). Product-
containing fractions
were combined and concentrated in vacuo to give the product after trituration
with diethyl ether
(106.4 g 40%). Total yield 212.3 g (80%); 1-H NMR (400 MHz, DMSO-d6) 6 7.97
(d, J = 2.4 Hz,
1H), 7.92 (dd, J = 1.9, 0.9 Hz, 1H), 7.13 (dq, J = 2.8, 0.9 Hz, 1H), 3.25 (s,
6H), 2.22 (d, J = 0.8
Hz, 3H); ESV-MS m/z 185.0 (M+1)+.
Step 2: 1-Benzy1-3-((dimethyboxoW-sulfanylidene)amino)-5-methylpyridin-1-ium
bromide
[00396]
To a solution of dimethyl((5-methyl-pyridin-3-yl)imino)-k6-sulfanone (105.9 g,
574.73
mmol) in MeCN (900 mL) was added BnBr (69 mL, 580 mmol). The mixture was
stirred at 100
C for 4 hours. The reaction mixture was allowed to cool to ambient temperature
and the resulting
precipitate collected by filtration, washing with cold MeCN. The product was
obtained as an off-
white solid (158.8 g, 78%);
NMR (400 MHz, DMSO-d6) 6 8.55 (s, 1H), 8.48 (t, J = 1.8 Hz,
178
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1H), 7.87 (t, J= 1.5 Hz, 1H), 7.58 - 7.49 (m, 2H), 7.49 - 7.37 (m, 3H), 5.67
(s, 2H), 3.44 (s, 6H),
2.41 (s, 3H). ESV-MS m/z 275.1 (M+1)+.
Step 3: ((l-benzyl-, 5-methyl-1,2,5,6-tetrahydropyridin-3-
yl)imino)dimethylulfanone
[00397] A solution of NaBH4 (43 g, 1.137 mol) in sodium hydroxide (1.6 L of
0.01 M 16.00
mmol) was added dropwise via syringe pump over 2 hours to a solution of 1-
benzy1-3-
((dimethyl(oxo)-k6-sulfanylidene)amino)-5-methylpyridin- 1 -ium bromide (200
g, 562.9 mmol) in
ethanol (600 mL) / water (600 mL) at 0 C under N2. The mixture was extracted
with MTBE (3 x
1.6L), the organics combined and washed with brine (1 x 600 mL), dried
(MgSO4), filtered and
concentrated in vacuo to give the desired product (142 g, 91 %); 1H NMR (400
MHz, Chloroform-
d) 6 7.40 - 7.17 (m, 5H), 5.18 - 5.10 (m, 1H), 3.58 (s, 2H), 3.08 (d, J = 1.9
Hz, 6H), 3.04 - 2.93
(m, 1H), 2.86 - 2.68 (m, 3H), 2.55 - 2.40 (m, 1H), 1.92 (dd, J= 11.0, 8.2 Hz,
1H), 0.95 (d, J= 6.9
Hz, 3H).ESV-MS m/z 279.1 (M+1)+.
Step 4: Dimethyb(5-methylpiperidin-3-yl)imino)P-sulfanone
[00398] Pd(OH)2, (59 g, 20% w/w, Degussa, 84.03 mmol) was transferred to a
nitrogen-filled
bottle and the vessel evacuated and re-filled with nitrogen. A solution of ((1-
benzyl-,5-methyl-
1,2,5,6-tetrahydropyridin-3-yl)imino)dimethyW-sulfanone (117 g, 420.2 mmol) in
methanol
(700 mL) was then added and the resulting solution degassed by vacuum/nitrogen
cycles (x 3).
The atmosphere was exchanged by vacuum/hydrogen cycles and the reaction
mixture was shaken
on a Parr hydrogenator for 16 hours. The reaction mixture was cooled to
ambient temperature then
was filtered through Celite and concentrated in vacuo to leave an orange oil
which was analysed
and showed incomplete reaction. The product was redissolved in methanol (700
mL) and added to
the Parr bottle containing dihydroxypalladium (59 g of 20 %w/w, 84.03 mmol).
The mixture was
then shaken at 50 C and 30 psi of molecular hydrogen overnight. The reaction
mixture was cooled
to ambient temperature then filtered through Celite and the filtrate
concentrated in vacuo to leave
an orange oil which was analysed by UPLC-MS - showing incomplete reaction. The
mixture was
again redissolved in methanol (700 mL) and added to a Parr bottle containing
dihydroxypalladium
(59 g of 20 %w/w, 84.03 mmol). The mixture was shaken at 50 C and under a 30
psi atmosphere
of molecular hydrogen on a Parr hydrogenator overnight. The mixture was cooled
to ambient
temperature then filtered through Celite before concentrating in vacuo to give
dimethyl((5-
methylpiperidin-3-yl)imino)-X,6-sulfanone (56.7 g, 71%); 1H NMR (500 MHz, DMSO-
d6) 6 3.54
(masked signal, 1H), 3.09 (tt, J= 10.8, 4.4 Hz, 1H), 2.95 (s, 6H), 2.89 - 2.74
(m, 2H), 2.11 (dd, J
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= 12.0, 10.3 Hz, 1H), 1.92 (dd, J= 12.1, 11.0 Hz, 1H), 1.84- 1.73 (m, 1H),
1.58- 1.44 (m, 1H),
0.89 (d, J = 12.4 Hz, 1H), 0.77 (d, J = 6.6 Hz, 3H).
[00399] The following compound was prepared using a methodology similar to the
one
described in Preparation 214:
Dimethyl((piperidin-3-yl)imino)-k6-sulfanone.
Preparation 15: 2,5-Dimethylpiperidine-3-carboxamide
0 0 0
NH4OH 2 H2, PtO2 NH 2
I
Step 1: 2,5-Dimethylnicotinamide
[00400] Methyl 2,5-dimethylpyridine-3-carboxylate (100 mg, 0.61 mmol) was
dissolved in
ammonium hydroxide (480 tL, 12.3 mmol) and the mixture heated to 70 C in a
sealed tube. After
16 hours the reaction was diluted in water and the mixture concentrated in
vacuo to give 2,5-
dimethylpyridine-3-carboxamide (91 mg, 100%) as a white solid; MS m/z: 151.0
(M+H)t
Step 2: 2,5-Dimethylpiperidine-3-carboxamide
[00401] 2,5-dimethylnicotinamide (99 mg, 0.66 mmol) and Pt02 (30.4 mg, 0.13
mmol) were
dissolved in methanol (3 mL) and 3M HC1 (1.1 mL, 3.30 mmol). The mixture was
degassed and
stirred under a balloon of H2 for 90 min before being passed through Celite
and the filtrate
concentrated in vacuo to give 2,5-dimethylpiperidine-3-carboxamide
(dihydrochloride salt) (150
mg, 99%); MS m/z: 157.0 (M+H)t
Preparation 16: N-W3S,5S)-4,4-Difluoro-5-
methylpiperidin-3-
yl)methyl)methanesulfonamide
i) N21-14
Cbz Cbz Cbz
N .1. 0 LIHMDS N = = N u
DAST separation N ii) MsCI
Ili) Et3SH, Pd(0A02
0 0 F F 0 F F 0 F F
Step 1: Benzyl 34(1,3-dioxoisoindolin-2-yl)methyl)-5-methyl-4-oxopiperidine-1-
carboxylate
[00402] Benzyl 3-methyl-4-oxo-piperidine-1-carboxylate (20 g, 0.08 mol) was
dissolved in
THF (300 mL) under N2. The solution was cooled to -78 C and LiHMDS (1M in
THF, 101.1
mL, 0.1 mol) was added dropwise over 20 minutes, keeping the temperature below
-70 C. After
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stirring at -78 C for 90 minutes, a solution of 2-(chloromethyl)isoindoline-
1,3-dione (23.7 g, 0.12
mol) in THF (200 mL) was added dropwise over 25 minutes, keeping the
temperature below -70
C. The reaction was stirred at -78 C for 1 hour then quenched at -78 C by
the addition of
saturated aqueous ammonium chloride solution (65 mL) and the mixture allowed
to warm to
ambient temperature. The reaction was repeated and the two mixtures obtained
were combined
and extracted with Et0Ac (300 mL). The organic phase was washed with saturated
aqueous
sodium bicarbonate solution (300 mL) and brine (300 mL), dried (Na2SO4),
filtered and
concentrated in vacuo. The residue was purified by chromatography (silica,
Et0Ac/Petroleum
ether elution). Product fractions were combined and concentrated in vacuo and
the residue
recrystallized from Et0Ac to give the product as a white solid (7.56 g, 23 %).
Step 2: Benzyl (3R,5S)-3-1(1,3-Dioxoisoindolin-2-yl)methy11-4,4-difluoro-5-
methyl-
piperidine-1-carboxylate
[00403] A flask was charged with benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-5-
methyl-4-
oxopiperidine-1-carboxylate (60 g, 0.15 mol) and cooled in an ice/water bath.
DAST (325 mL, 2.5
mol) was added in one portion and the mixture stirred at ambient temperature
for 3 days. The
resulting yellow solution was diluted with DCM (1 L) and slowly added to a
mixture of ice/water
and solid sodium bicarbonate with overhead stirring. The temperature remained
below 0 C and
additional sodium bicarbonate was added to maintain a pH of 7-8. The mixture
was warmed to
ambient temperature and the layers separated. The aqueous phase was extracted
with DCM (2 L).
The combined organics were washed with brine, dried (Na2SO4), filtered and
concentrated in
vacuo. The residue was purified by chromatography (silica, Et0Ac/Petroleum
ether elution).
Product fractions were combined and concentrated in vacuo. The product benzyl
34(1,3-
dioxoisoindolin-2-yl)methyl)-4,4-difluoro-5-methylpiperidine- 1 -carboxylate,
was obtained as a
glass (32.5 g, 51 %); 1H NMIt (400 MHz, chloroform-d) 6 7.89 ¨ 7.64 (4H, m),
7.42 ¨ 7.11 (5H,
m), 5.15 ¨ 5.03 (2H, m), 4.39-4.07 (3H, m), 3.83 ¨3.66 (1H, m), 2.97 ¨ 2.60
(2H, m), 2.56 ¨ 2.31
(1H, m), 2.08 ¨ 1.89 (1H, m), 1.05 (3H, d) as a mixture of isomers.
[00404] Preparative chiral supercritical fluid chromatography (conditions:
ChiralpakAC 5[tm,
CO2/iPrOH 90/10, 230nm) was used to isolate the single enantiomer benzyl
(3R,5S)-3-[(1,3-
dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylate,
(98.7 % ee).
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Step 3: Benzyl (3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methyl-piperidine-1-
carboxylate
[00405] To a suspension of benzyl (3R,5S)-3-[(1,3-dioxoisoindolin-2-
yl)methyl]-4,4-difluoro-
5-methyl-piperidine-1-carboxylate (9.6 g, 22.4 mmol) in ethanol (144 mL) was
added hydrazine
hydrate (8.5 mL, 112 mmol). The reaction mixture was heated to reflux for 5
hours then allowed
to cool to ambient temperature overnight. The resulting suspension was
filtered and the precipitate
washed with Et0H (x 2). The filtrate was loaded onto ion-exchange cartridges
(50 g x 10). The
cartridges were washed with Me0H/DCM mixtures (filtrates discarded), then with
2M methanolic
ammonia solution. The filtrates were combined and concentrated in vacuo. The
residue was taken
up in methanol and concentrated in vacuo (x 2), then treated with heptane and
concentrated in
vacuo. The resulting yellow oil was dried under vacuum overnight to give the
product as a solid
(6.77 g), which was taken directly on to the next reaction; 111NMR (400 MHz,
DMSO-d6) 6 7.48
¨7.17 (m, 5H), 5.11 (s, 2H), 4.41 (ddt, 1H), 4.02 (d, 1H), 2.98 (dd, 1H), 2.64
(s, 2H), 2.41 (dd,
1H), 2.15¨ 1.78 (m, 2H), 1.50 (s, 2H), 0.93 (d, 3H); MS m/z: 299 (M+H)t
Step 4: Benzyl (3S,5S)-4,4-difluoro-3-(methanesulfonamidomethyl)-5-methyl-
piperidine-1-
carboxylate
[00406] Benzyl (3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methyl-piperidine-1-
carboxylate (6.6
g, 22 mmol) was dissolved in DCM (66 mL) and cooled in an ice bath. The
internal temperature
reached was 3 C. Et3N (3.4 mL, 24 mmol) was added with stirring.
Methanesulfonyl chloride
(1.88 mL, 24 mmol) was added over 5 minutes, at such a rate to keep the
internal temperature
below 10 C. After 30 minutes, the ice bath was removed. The solution was
warmed up to ambient
temperature and quenched with a saturated aqueous NaHCO3 solution (66 mL). The
layers were
separated and the aqueous phase extracted with DCM (33 mL). The combined
organics were dried
over MgSO4, filtered and concentrated in vacuo. The residue was purified by
chromatography
(silica; 0 to 100% Et0Ac /Petroleum ether gradient elution). The product
fractions were combined
and concentrated in vacuo. The residue was dried overnight under vacuum to
give a white solid
(7.92 g; 95%); 1H NMR (400 MHz, DMSO-d6) 6 7.45 ¨ 7.31 (m, 5H), 7.31 ¨7.19 (m,
1H), 5.12
(s, 2H), 4.37 (d, 1H), 4.18 ¨ 3.94 (m, 1H), 3.38 (ddd, 1H), 3.00 ¨ 2.80 (m,
4H), 2.68 (s, 2H), 2.15
(s, 2H), 0.95 (d, 3H); MS m/z: 377 (M+H)t
Step 5: N-(((3S,5S)-4,4-Difluoro-5-methylpiperidin-3-
yl)methyl)methanesulfonamide
[00407] To a solution of benzyl (3S,5S)-4,4-difluoro-3-
(methanesulfonamidomethyl)-5-
methyl-piperidine-1-carboxylate (7.54 g, 20 mmol) in DCM (113 mL) was added
Et3N (8.38 mL,
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60 mmol), followed by Pd(OAc)2 (1.799 g, 8 mmol). Et3SiH (19.20 mL, 120 mmol)
was added
over 5 minutes. The solution was stirred at ambient temperature for 1 hour
then separated into 6
equal portions and loaded onto ion-exchange cartridges (50 g). The cartridges
were washed with
DCM, 1:1 MeOH:DCM and methanol. The filtrates were discarded. The cartridges
were washed
with 2M methanolic ammonia solution. The filtrates were combined and
concentrated in vacuo.
The residue was azeotroped with DCM then taken up in methanol (45 mL) and
stirred with SPM32
(3-mercaptopropyl ethyl sulfide silica) for 2 hours at ambient temperature,
then at 50 C for 1 hour.
The mixture was cooled and filtered through Celite and the filtrate
concentrated in vacuo. The
residue was taken up in DCM and concentrated in vacuo. The residue was dried
overnight under
vacuum to give N-(((3S,5S)-4, 4-difluoro-5-methylpiperidin-3-
yl)methyl)methanesulfonamide as a
white solid (4.40 g, 91%); NMR (400 MHz, DMSO-d6) 6 7.10 (t, 1H), 3.43 ¨
3.33 (m, 1H),
3.26 ¨ 3.10 (m, 1H), 2.93 ¨ 2.88 (m, 4H), 2.79 (dtd, 1H), 2.38 ¨ 2.20 (m, 2H),
2.13¨ 1.78 (m, 2H),
0.89 (d, 3H); MS m/z: 243.0 (M+H)t
Preparation 17: N-(Pyrrolidin-3-ylmethyl)methanesulfonamide
o
f-%\ (i) MeS02C1 HN
(ii) TFA, DCM NH
NH2
0
Step 1: tert-Butyl 3-(methanesulfonamidomethyl)pyrrolidine-1-carboxylate
[00408] Methanesulfonyl chloride (222 mg, 150 L, 1.938 mmol) was added to a
stirred
solution of tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (300 mg, 1.498
mmol) and
triethylamine (232.3 mg, 320 L, 2.296 mmol) in THF (10 mL) under an
atmosphere of nitrogen
and the reaction was stirred at ambient temperature for 1.5 hours. The
reaction was diluted with
DCM and saturated aqueous NaHCO3 and the mixture was stirred for 10 minutes.
The layers were
separated and the aqueous layer extracted with DCM (x 2). The combined organic
extracts were
dried (MgSO4), filtered and concentrated in vacuo to give tert-butyl 3-
(methanesulfonamidomethyl)pyrrolidine-1-carboxylate as a pale yellow oil that
was deprotected
assuming 100% yield and purity; 1-H NMR (500 MHz, DMSO-d6) 6 7.11 (t, J= 6.2
Hz, 1H), 3.40
- 3.35 (m, 1H), 3.32 - 3.28 (m, 1H), 3.23 - 3.15 (m, 1H), 2.95 -2.93 (m, 3H),
2.89 (s, 3H), 2.31 -
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2.26 (m, 1H), 1.93 - 1.88 (m, 1H), 1.65 - 1.52 (m, 1H), 1.40 (s, 9H); ESV-MS
m/z calc. 278.13004,
found 223.1 (M+1)
Step 2: N-(Pyrrolidin-3-ylmethyl)methanesulfonamide
[00409] TFA (2.960 g, 2 mL, 25.96 mmol) was added to a stirred solution of
tert-butyl 3-
(methanesulfonamidomethyl)pyrrolidine-1 -carboxylate (417 mg, 1.498 mmol) in
DCM (20 mL)
and the reaction mixture was stirred at ambient temperature for 15 hours. The
solvent was removed
in vacuo and the residue azeotroped with DCM (x 2) and diethyl ether (x 2).
The residue was
passed through a 10 g SCX-2 cartridge and washed with Me0H/DCM mixtures. The
product was
eluted by washing the cartridge with 2M NH3 in Me0H/DCM mixtures. The solvent
was removed
in vacuo to give N-(pyrrolidin-3-ylmethyl)methanesulfonamide (227.4 mg, 85%)
as a pale yellow
solid; 1-E1 NMR (500 MHz, chloroform-d) 6 3.16 (qd, J = 12.3, 6.5 Hz, 2H),
3.09 - 3.03 (m, 2H),
2.98 (s, 3H), 2.94 - 2.89 (m, 1H), 2.75 (dd, J = 10.7, 5.0 Hz, 1H), 2.40 -
2.32 (m, 1H), 2.04 - 1.96
(m, 1H), 1.55 - 1.48 (m, 1H). ; ESV-MS m/z 179.2 (M+1)
Preparation 18: 4-Pyrrolidin-3-y1-1H-pyrazole
O'B ,0 HN ¨N
(i) Suzuki
(ii) TFA, DCM
(iii) H2, Pd/C, Me0H
)7-0 NH
Step 1: tert-Butyl 3-(1H-pyrazol-4-y1)-2,5-dihydropyrrole-1-carboxylate
[00410] tert-Butyl 4-bromopyrazole-1-carboxylate (230 mg, 0.931 mmol) , tert-
butyl 3-
(4,4, 5,5 -tetram ethyl-1,3 ,2-di oxab orol an-2-y1)-2,5 -di hy dropyrrol e-l-
carb oxyl ate (250 mg, 0.847
mmol) and potassium carbonate (1.3 mL of 2M, 2.60 mmol) were combined in
dioxane (3 mL)
and the mixture de-gassed (x 2 vacuum cycles). Pd(dppf)C12.DCM (70 mg, 0.086
mmol) was
added and the mixture de-gassed (x 2 vacuum cycles) then heated at 90 C
overnight. The reaction
mixture was partitioned between Et0Ac and water. The organic phase was dried
(Na2SO4), filtered
and concentraed in vacuo. The residue was purified by chromatography (silica,
0-100%
Et0Ac/Petroleum ether gradient elution). Product fractions were combined and
concentrated to
give the product as a pale yellow film (65 mg, 33%) that was taken on to the
next reaction. ESV-
MS m/z 236.0 (M+1)
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Steps 2 and 3: 4-Pyrrolidin-3-y1-1H-pyrazole
[00411] tert-Butyl 3 -(1H-pyrazol-4-y1)-2, 5-di hydropyrrol e-l-carb oxyl
ate (550 mg, 2.338
mmol) was dissolved in DCM (10 mL) and TFA added. After 1 hour the reaction
mixture was
concentrated in vacuo and the residue azeotroped with DCM (x 2). The residue
was taken up in
methanol (10 mL) and the solution degassed (x 3 vacuum - N2 cycles). Pd on C,
wet, Degussa (200
mg of 10 %w/w, 0.188 mmol) was added and the mixture degassed (x 3 cycles).
The N2 atmosphere
was replaced with hydrogen (x 3 cycles) and the mixture stirred at ambient
temperature. After 90
minutes the reaction mixture was filtered over Celite, washing with methanol.
The filtrate was
concentrated in vacuo (cold water bath) to give crude 4-pyrrolidin-3-y1-1H-
pyrazole
(trifluoroacetate salt) (600 mg, quantitative yield); ESV-MS m/z 136.0 (M+1)
Preparation 19: (E)-2-(2-Ethoxyviny1)-4-(methylthio)pyrimidine
0
N
,
-N S
CI -N
[00412] To a suspension of 2-chloro-4-(methylthio)pyrimidine (56.1 g, 349.3
mmol) and 2 M
aq. Na2CO3 (524 mL, 1.05 mol) in 1,2-dimethoxyethane (730 mL) was added 2-[(E)-
2-
ethoxyviny1]-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (76.1 g, 384 mmol).
Pd(PPh3)4 (20.2 g, 17.5
mmol) was added and the mixture degassed. The reaction was placed under a
nitrogen atmosphere
and heated at reflux for 4 hours. The mixture was cooled to ambient
temperature and partitioned
between Et0Ac (1.1 L) and water (560 mL). The organic layer was washed with
water (2 x 560
mL), the combined organic layers were re-extracted with Et0Ac (280 mL) and the
combined
organic phases were washed with brine (x 1), dried (MgSO4), filtered and
concentrated in vacuo.
The residue was purified by column chromatography (silica, eluting with 0 to
25%
Et0Ac/petroleum ether) to give (E)-2-(2-ethoxyviny1)-4-(methylthio)pyrimidine
as a pale yellow,
crystalline solid (62.4 g, 91%); 1-H NMR (500 MHz, Chloroform-d) 6 8.18 (d, J
= 5.5 Hz, 1H),
7.95 (d, J = 12.6 Hz, 1H), 6.85 (d, J = 5.5 Hz, 1H), 5.91 (d, J = 12.6 Hz,
1H), 4.02 (q, J = 7.0 Hz,
2H), 2.56 (s, 3H), 1.40 (t, J= 7.0 Hz, 3H); ES+ [M+H]= 197.1.
Preparation 20: 2-chloro-4-{6-cyclopropylimidazo[1,2-alpyridin-3-yl}pyrimidine
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Pd(PPh3)4 N
CI
chloro(propan-2-
N/ >-B(OH)2 ____ / Br yl)magnesium; N
Pd(dppOCl2 CH2C12, N\ NBS N\ N chlorolithium
\ K3PO4
DCM
dioxaneNCI
\
Br
THF
[00413]
Step 1: 6-Cyclopropylimidazo[1,2-a]pyridine. Into a 150-mL round-bottom flask,
was
placed 6-bromoimidazo[1,2-a]pyridine (5 g, 22.84 mmol, 1 equiv, 90%),
cyclopropylboronic acid
(3.1 g, 34.26 mmol, 1.50 equiv, 95%), Pd(dppf)C12.CH2C12 (2.0 g, 2.33 mmol,
0.10 equiv, 95%),
dioxane (20 mL, 224.28 mmol, 9.82 equiv, 95%), K3PO4 (10.2 g, 45.68 mmol, 2.00
equiv, 95%).
The resulting solution was stirred for overnight at 100 degrees C in an oil
bath. The resulting
mixture was concentrated. The residue was applied onto a silica gel column
with ethyl
acetate/petroleum ether (1/5). This resulted in 3.6 g (89.67%) of 6-
cyclopropylimidazo[1,2-
a]pyridine as a white solid.
[00414]
Step 2: 3-Bromo-6-cyclopropylimidazo[1,2-a]pyridine. Into a 150-mL round-
bottom
flask, was placed 6-cyclopropylimidazo[1,2-a]pyridine (3.6 g, 20.48 mmol, 1
equiv, 90%), NBS
(3.8 g, 20.28 mmol, 0.99 equiv, 95%), DCM (20 mL, 298.87 mmol, 14.59 equiv,
95%). The
resulting solution was stirred for 3 hr at 25 degrees C. The resulting mixture
was concentrated.
The residue was applied onto a silica gel column with ethyl acetate/petroleum
ether (1/5). This
resulted in 4.3 g (79.70%) of 3-bromo-6-cyclopropylimidazo[1,2-a]pyridine as a
white solid.
[00415] Step 3: 2-Chloro-4-{6-cyclopropylimidazo[1,2-a]pyridin-3-
yl}pyrimidine. To a
stirred solution of 3-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.5 g, 5.694
mmol, 1 equiv,
90%) in THF (10 mL, 117.259 mmol, 21.0 equiv, 95%) was added iPrMgCl.LiC1
(1.74 g, 11.388
mmol, 2 equiv, 95%) dropwise at -10 degrees Celsius under nitrogen atmosphere.
The resulting
mixture was stirred for 2 h at 0 degrees Celsius under nitrogen atmosphere.
The above mixture
was added into a stirred mixture of 2,4-dichloropyrimidine (1.07 g, 6.824
mmol, 1.20 equiv, 95%)
and Pd(PPh3)4 (0.35 g, 0.285 mmol, 0.05 equiv, 95%) in THF (10 mL, 117.259
mmol, 21.0 equiv,
95%) at room temperature. The resulting mixture was stirred for additional 4 h
at 70 degrees
Celsius. The resulting mixture was concentrated. The residue was applied onto
a silica gel column
with ethyl acetate/petroleum ether (1/10). This resulted in 1 g (58.39%) of 2-
chloro-446-
cyclopropylimidazo[1,2-a]pyridin-3-yl]pyrimidine as a white solid.
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[00416] The following compounds were prepared using a methodology similar to
the one
described in Preparation 20:
2-Chloro-4- { 6 -chloroimidazo[1,2-a]pyridin-3 -yl}pyrimidine
/yCkN
N, N
\
CI
Preparation 21: 2-chloro-4-1(E)-2-ethoxyetheny11-6-methylpyrimidine
CI NO
[00417] To a stirred solution of 2,4-dichloro-6-methylpyrimidine (246.88
mg, 1.439 mmol, 1.20
equiv, 95%), 2-[(E)-2-ethoxyethenyl] -4,4,5,5-tetram ethyl-1,3 ,2-di oxab orol
ane (250 mg, 1.199
mmol, 1 equiv, 95%) and K3PO4 (535.84 mg, 2.398 mmol, 2.00 equiv, 95%) in MeCN
(12.45 mL,
303.230 mmol, 187.63 equiv, 95%) and H20 (4 mL, 210.932 mmol, 364.96 equiv,
95%) were
added SPhos (36.27 mg, 0.084 mmol, 0.07 equiv, 95%) and Pd(Ac0)2 (8.50 mg,
0.036 mmol,
0.03 equiv, 95%) at room temperature under nitrogen atmosphere. The resulting
mixture was
stirred for overnight at room temperature under nitrogen atmosphere. The
resulting mixture was
concentrated to a small volume. The resulting mixture was diluted with brine
(20 mL). The
resulting mixture was extracted with Et0Ac (3 x 50 mL). The combined organic
layers were
washed with brine (2x20 mL), dried over anhydrous MgSO4. After filtration, the
filtrate was
concentrated under reduced pressure. The residue was purified by silica gel
column
chromatography, eluted with PE/Et0Ac (5:1) to afford 2-chloro-4-[(E)-2-
ethoxyetheny1]-6-
methylpyrimidine(100mg,37.78%) as a light yellow oil.
Preparation 22: 2-chloro-4-16-(3,3-difluoroazetidin-1-yl)imidazo[1,2-alpyridin-
3-y11-6-
methylpyrimidine
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JN
NBS
)1=('cla2
(tdPbhac
N7".--"-r'N CI
F dioxane/H20 Br HN Pd/C
+ 11 Cs2CO3 Me0H
02N N F 0
1/4_14
F dioxane 2N N H2N N
CI N
[00418]
Step 1: 5-(3,3-difluoroazetidin-1-y1)-2-nitropyridine. To a stirred solution
of 5-bromo-
2-nitropyridine(500 mg, 2.340 mmol, 1 equiv, 95%), 3,3-difluoroazetidine
hydrochloride (350.95
mg, 2.574 mmol, 1.1 equiv, 95%) and Cs2CO3 (4012.66 mg, 11.700 mmol, 5.00
equiv, 95%) in
dioxane (37.50 mL, 425.622 mmol, 179.71 equiv, 95%) was added Pd2(dba)3
(112.78 mg, 0.117
mmol, 0.05 equiv, 95%) and XantPhos (142.52 mg, 0.234 mmol, 0.10 equiv, 95%)
at room
temperature under nitrogen atmosphere. The resulting mixture was stirred for 3
h at 100 degrees
C under nitrogen atmosphere. The resulting mixture was concentrated under
reduced pressure.
The residue was purified by silica gel column chromatography, eluted with
PE/Et0Ac (1:1) to
afford 5-(3,3-difluoroazetidin-1-y1)-2-nitropyridine(200mg,27.81%) as a light
yellow solid.
[00419]
Step 2: 5-(3,3-difluoroazetidin- 1 -yl)pyridin-2-amine. To a stirred solution
of 543,3-
difluoroazetidin-1-y1)-2-nitropyridine (175 mg, 0.569 mmol, 1 equiv, 70%) in
Me0H (56.00 mL,
1747.713 mmol, 2307.89 equiv, 95%) was added Pd/C (318.89 mg, 2.847 mmol, 5
equiv, 95%) in
portions at room temperature under nitrogen atmosphere. The resulting mixture
was stirred for
overnight at room temperature under hydrogen atmosphere. The resulting mixture
was filtered, the
filter cake was washed with Me0H (3x30 mL). The filtrate was concentrated
under reduced
pressure. The crude product/ resulting mixture was used in the next step
directly without further
purification.
[00420] Step 3: 2-chloro-446-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-
3-y1]-6-
methylpyrimidine. To a stirred solution of 2-chloro-4-[(E)-2-ethoxyetheny1]-6-
methylpyrimidine
(550 mg, 2.630 mmol, 1 equiv, 95%) in H20 (18 mL, 999.151 mmol, 379.87 equiv,
9%) and H20
(18 mL, 999.151 mmol, 379.87 equiv, 9%) was added NBS (492.78 mg, 2.630 mmol,
1 equiv,
95%) at room temperature. The resulting mixture was stirred for 1 h at room
temperature. To the
above mixture was added 5-(3,3-difluoroazetidin-1-yl)pyridin-2-amine (666.51
mg, 3.419 mmol,
1.3 equiv, 95%). The resulting mixture was stirred for additional 2.5 h at 85
degrees C. The
resulting mixture was diluted with Et0Ac (20 mL). The mixture was neutralized
to pH 7 with
saturated Na2CO3 (aq.). The resulting mixture was extracted with Et0Ac (3 x 30
mL). The
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combined organic layers were washed with brine (2x50 mL), dried over anhydrous
MgSO4. After
filtration, the filtrate was concentrated under reduced pressure. The residue
was purified by silica
gel column chromatography, eluted with CH2C12 / Me0H (20:1). This resulted in
2-chloro-4-[6-
(3,3 -difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3 -y1]-6-
methylpyrimidine(290mg,31.85%) as a
light yellow solid.
[00421] The following compounds were prepared using a methodology similar to
the one
described in Preparation 22:
2-Chloro-446-(3-fluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidine
Preparation 23: 546-(azetidin-1-yl)imidazo[1,2-alpyridin-3-y11-2-
chloropyrimidine
Pd(PPh3)4
NYCI
N7Br chloro(propan-2-
Pd2(dba)3
I\1/ BINAP
NBS yl)magnesium;
chlorolithium
LINN
tBuONa, \ DCM \
toluene
-1
Br
NIL]
THF
[00422] Step 1: 1-{imidazo[1,2-a]pyridin-6-yl}azetidine. Into a 500 mL
round-bottom flask
were added 6-bromoimidazo[1,2-a]pyridine(3.5 g, 15.99 mmol, 1 equiv, 90%),
azetidine(1441.3
mg, 23.98 mmol, 1.50 equiv, 95%), toluene (300 mL, 2678.69 mmol, 167.55 equiv,
95%), BINAP
(1047.9 mg, 1.60 mmol, 0.10 equiv, 95%) and t-BuONa(3234.5 mg, 31.97 mmol,
2.00 equiv, 95%)
at room temperature. The resulting mixture was stirred for overnight at 100
degrees C under
nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The
residue was
purified by silica gel column chromatography, eluted with PE/Et0Ac (5:1) to
afford 1-
[imidazo[1,2-a]pyridin-6-yl]azetidine(2.5g,78.72%) as a green solid.
[00423] Step 2: 1-{3-bromoimidazo[1,2-a]pyridin-6-yl}azetidine. Into a 25
mL round-bottom
flask were added 1-[imidazo[1,2-a]pyridin-6-yl]azetidine (1 g, 5.03 mmol, 1
equiv, 87.2%),
NBS(896.0 mg, 4.78 mmol, 0.95 equiv, 95%) and DCM (60 mL, 896.61 mmol, 178.11
equiv,
95%) at room temperature. The resulting mixture was stirred for overnight at
room temperature
under nitrogen atmosphere. The resulting mixture was concentrated under
reduced pressure. The
residue was purified by silica gel column chromatography, eluted with PE/Et0Ac
(5:1) to afford
143-bromoimidazo[1,2-a]pyridin-6-yl]azetidine(1.1 g, 56.25%) as a green solid.
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[00424] Step 3: 5- [6 -(azetidin-1 -yl)imidazo[1,2 -y1]-2-
chloropyrimidine. To a
stirred solution of 1[3-bromoimidazo[1,2-a]pyridin-6-yl]azetidine(200 mg,
0.777 mmol, 1 equiv,
98%) in THF(20 mL, 234.517 mmol, 301.66 equiv, 95%) was added dropwise at -10
degrees C
under N2 atmosphere. Chloro(propan-2-yl)magnesium chlorolithium (1 mL, 1.084
mmol, 1.39
equiv, 17.5%) was added. The resulting mixture was stirred for 2 h at 0
degrees C under N2
atmosphere. The above mixture was added into a stirred mixture of 2,4-
dichloropyrimidine(182.86
mg, 1.166 mmol, 1.50 equiv, 95%) and Pd(PPh3)4(47.28 mg, 0.039 mmol, 0.05
equiv, 95%) in
THF at room temperature. The resulting mixture was stirred for additional 4 h
at 80 degrees C.
The reaction was quenched with sat. NH4C1 (aq.) at room temperature. The
aqueous layer was
extracted with Et0Ac (3x20 mL). The resulting mixture was concentrated under
reduced pressure.
The residue was purified by silica gel column chromatography, eluted with
EA:PE (1:1) to afford
4[6-(azetidin-1-yl)imidazo[1,2-a]pyridin-3-y1]-2-chloropyrimidine (120 mg,
19.61%) as a green
solid.
Preparation 24: 5-(3-methyl-1H-pyrazol-4-yl)piperidin-3-ol
4
Pd(dppf)Cl2 ____________ HO CH2Cl2 0
0 1\1\1H =no/ H NH NaBH,
H NH Pd/C
I 0
H 0:, Br K2CO3 I MeCN Nj 0 Et0H N Me0H
Ho NH
Ph) Br Ph)
[00425]
Step 1: 5-(3 -Methy1-1H-pyrazol-4-y1)pyri din-3 -ol . A mixture of 5-b rom
opyri din-3 -ol
(10 g, 54.599 mmol, 1 equiv, 95%), Pd(dppf)C12.CH2C12 (2.35 g, 2.730 mmol,
0.05 equiv, 95%),
K2CO3 (11.91 g, 81.898 mmol, 1.50 equiv, 95%) and 3-methy1-4-(4,4,5,5-
tetramethy1-1,3,2-
dioxaborolan-2-y1)-1H-pyrazole (14.35 g, 65.518 mmol, 1.2 equiv, 95%) in
dioxane (150.01 mL,
1682.194 mmol, 30.81 equiv, 95%) and H20 (29.99 mL, 1664.971 mmol, 28.97
equiv, 95%) was
stirred for overnight at 100 degrees C under nitrogen atmosphere. The
resulting mixture was
concentrated under reduced pressure. The residue was purified by silica gel
column
chromatography, eluted with CH2C12/Me0H (10:1) to afford 5-(3-methy1-1H-
pyrazol-4-
y1)pyridin-3-ol (6.5g,61.16%) as a brown solid.
[00426]
Step 2: 1-B enzy1-3 -hydroxy-5-(3 -methy1-1H-pyraz ol-4-yl)pyri din-l-ium
bromide. A
mixture of 5-(3-methyl-1H-pyrazol-4-y1)pyridin-3-ol (6.2 g, 31.851 mmol, 1
equiv, 90%) and
BnBr (6.88 g, 0.038 mmol, 1.2 equiv, 95%) in MeCN (300.00 mL, 6942.365 mmol,
170.23 equiv,
95%) was stirred for overnight at 60 degrees C under hydrogen atmosphere. The
resulting mixture
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was concentrated under reduced pressure. The residue was purified by silica
gel column
chromatography, eluted with CH2C12 / Me0H (85:15) to afford 1-benzy1-3-hydroxy-
5-(3-methy1-
1H-pyrazol-4-y1)pyridin- -ium bromide (9g,73.45%) as a brown solid.
[00427] Step 3: 1-B enzy1-5 -(3 -m ethy1-1H-pyrazol -4-y1)-1,2,3 ,6-tetrahy
dropyri din-3 -ol . A
mixture of 1-b enzy1-3 -hydroxy-5 -(3 -methy1-1H-pyrazol-4-y1)pyridin-1-ium
bromide (6.5 g,
16.896 mmol, 1 equiv, 90%) and NaBH4 (2.68 g, 67.296 mmol, 3.98 equiv, 95%) in
Et0H (260.00
mL, 5643.864 mmol, 251.64 equiv, 95%) was stirred for overnight at room
temperature under
nitrogen atmosphere. The reaction was quenched with sat. NH4C1 (aq.) at room
temperature. The
resulting mixture was concentrated under reduced pressure. The residue was
purified by silica gel
column chromatography, eluted with CH2C12/Me0H (10:1) to afford 1-benzy1-5-(3-
methy1-1H-
pyrazol-4-y1)-1,2,3,6-tetrahydropyridin-3-ol (5g,98.88%) as a yellow oil.
[00428] Step 4: 5-(3-Methyl-1H-pyrazol-4-yl)piperidin-3-ol. A mixture of 1-
benzy1-5-(3-
methy1-1H-pyrazol-4-y1)-1,2,3,6-tetrahydropyridin-3-ol (3.2 g, 10.692 mmol, 1
equiv, 90%) and
Pd/C (1137.89 mg, 1.069 mmol, 0.10 equiv, 10%) in Me0H (200.00 mL, 5929.777
mmol, 438.89
equiv, 95%) was stirred for 4 h at room temperature under hydrogen atmosphere.
The resulting
mixture was filtered, the filter cake was washed with Me0H (3x5 mL). The
filtrate was
concentrated under reduced pressure to afford 5-(3-methy1-1H-pyrazol-4-
y1)piperidin-3-
ol(2g,92.88%) as a colorless semi-solid.
[00429] The following compounds were prepared using a methodology similar to
the one
described in Preparation 24:
3 -(3 -Fluoro-1H-pyrazol-4-y1)-5 -methylpiperi dine
NH
HN
F
Example 1: 3-(4-(34(S-Methylsulfonimidoyl)methyl)piperidin-1-yl)pyrimidin-2-
y1)-6-
(trifluoromethyl)imidazo[1,2-a] pyridine, 1-4
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N
NN
\ /NJ
[00430] 3-(4-Chloropyrimidin-2-y1)-6-(trifluoromethyl)imidazo[1,2-
c]pyridine (13.2 mg, 0.05
mmol), 3-((S-methylsulfonimidoyl)methyl)piperidine (8 mg, 0.045 mmol),
diisopropylethylamine
(8 tL, 0.045 mmol) in DMF were heated at 80 C. After 20 mins the reaction was
cooled to room
temperature and the mixture was filtered and purified by reverse phase
chromatography (C18;
MeCN/water/0.05% TFA as eluent) to afford the trifluoroacetic acid salt of 3-
(4-(3-((S-
methylsulfonimidoyl)methyl)piperidin-1-yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[1,2-
c]pyridine (12.7 mg, 40%).
[00431] The following compounds were prepared using a methodology similar to
the one
described in Example 1:
8-Methylsulfony1-142-[6-(trifluoromethyl)imidazo[1,2-c]pyridin-3-yl]pyrimidin-
4-y1]-1,8-
diazaspiro[4.5]decane, 1-7
N-R-4,4-Difluoro-5-methy1-14246-(trifluoromethyl)imidazo[1,2-c]pyridin-3-
yl]pyrimidin-4-y1]-
3-piperidyl]methyl]methanesulfonamide, 1-8
N-R2S)-442-(6-Chloroimidazo[1,2-c]pyridin-3-yl)pyrimidin-4-yl]morpholin-2-
yl]methyl]methanesulfonamide, 1-19 (using 6-chloro-3-(4-chloropyrimidin-2-
yl)imidazo[1,2-c]pyridine)
442-(6-Chloroimidazo[1,2-c]pyridin-3-yl)pyrimidin-4-y1]-2-(1H-pyrazol-4-
yl)morpholine, 1-20
(using 6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-c]pyridine)
6-Chloro-3-(4-(3-((methylsulfonimidoyl)methyl)piperidin-1-yl)pyrimidin-2-
yl)imidazo[1,2-
c]pyridine, 1-21 (using 6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-
c]pyridine)
442-(6-Chloro-7-fluoro-imidazo[1,2-c]pyridin-3-yl)pyrimidin-4-y1]-2-(1H-
pyrazol-4-
yl)morpholine, 1-23 (using 6-chloro-3-(4-chloropyrimidin-2-y1)-7-fluoro-
imidazo[1,2-
c]pyridine)
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442-(6-Bromo-7-fluoro-imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1]-2-(1H-pyrazol-
4-
yl)morpholine, 1-24 (using 6-bromo-7-fluoro-3-(4-methylsulfanylpyrimidin-2-
yl)imidazo[1,2-a]pyridine)
N-[[ 1 -[2-(6-Bromo-7-fluoro-imidazo[ 1,2-c]pyridin-3 -yl)pyrimidin-4-
yl]pyrrolidin-3 -
yl]methyl]methanesulfonamide 1-25 (using 6-bromo-7-fluoro-3-(4-
methylsulfanylpyrimidin-2-yl)imidazo[1,2-a]pyridine)
142-(6-Chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1]-1,4-diazepan-5-one 1-
26 (using 6-
chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine);
6-Chloro-34443-(1H-pyrazol-4-yl)pyrrolidin-1-yl]pyrimidin-2-yl]imidazo[1,2-
a]pyridine 1-27
(using 6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine)
6-Chloro-34443-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]imidazo[1,2-
a]pyridine 1-28
(using 6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine)
6-Chloro-34443-dimethylphosphory1-5-(1H-pyrazol-4-y1)-1-piperidyl]pyrimidin-2-
yl]imidazo[1,2-a]pyridine 1-29 (using 6-chloro-3-(4-chloropyrimidin-2-
yl)imidazo[1,2-
a]pyridine)
((1-(2-(6-Chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-
yl)imino)dimethyl-X,6-
sulfanone 1-30 (using 6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-
a]pyridine)
N-R-14446-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-y1]-4,4-
difluoro-5-methy1-
3-piperidyl]methyl]methanesulfonamide, 1-41 (using 3-(2-chloropyrimidin-4-y1)-
6-
(difluoromethyl)imidazo[1,2-a]pyridine);
6-Chloro-7-fluoro-34443-(1H-imidazol-4-y1)-2,5-dimethyl-piperazin-1-
yl]pyrimidin-2-
yl]imidazo[1,2-a]pyridine 1-42 (using 6-chloro-3-(4-chloropyrimidin-2-y1)-7-
fluoro-
imidazo[1,2-a]pyridine)
74246-(Trifluoromethypimidazo[1,2-a]pyridin-3-yl]pyrimidin-4-y1]-1,2,5,6,8,8a-
hexahydroimidazo[1,5-a]pyrazin-3-one 1-43 (using 3-(4-chloropyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[1,2-a]pyridine)
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2-(1H-Pyrazol-4-y1)-44446-(trifluoromethyl)imidazo[1,2-c]pyridin-3-
yl]pyrimidin-2-
yl]morpholine 1-44 (using 3-(2-chloropyrimidin-4-y1)-6-
(trifluoromethyl)imidazo[1,2-
c]pyridine)
(3S)-142-(6-Chloro-7-fluoro-imidazo[1,2-c]pyridin-3-yl)pyrimidin-4-
yl]piperidine-3-
carboxamide 1-48 (using 6-chloro-3-(4-chloropyrimidin-2-y1)-7-fluoro-
imidazo[1,2-
c]pyridine)
((1-(2-(6-Chloro-7-fluoroimidazo[1,2-c]pyridin-3-yl)pyrimidin-4-y1)piperidin-3-
yl)imino)dimethyW-sulfanone 1-49 (using (using 6-chloro-3-(4-chloropyrimidin-2-
y1)-7-
fluoro-imidazo[1,2-c]pyridine)
142-(6-Chloroimidazo[1,2-c]pyridin-3-yl)pyrimidin-4-y1]-2,5-dimethyl-
piperidine-3-
carboxamide 1-50 (using 6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-
c]pyridine);
142-(6-Chloroimidazo[1,2-c]pyridin-3-yl)pyrimidin-4-y1]-2,5-dimethyl-
piperidine-3-
carboxamide 1-51 (using 6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-
c]pyridine)
142-(6-Chloro-7-fluoro-imidazo[1,2-c]pyridin-3-yl)pyrimidin-4-y1]-2,5-dimethyl-
piperidine-3-
carboxamide 1-52 and 142-(6-chloro-7-fluoro-imidazo[1,2-c]pyridin-3-
yl)pyrimidin-4-
y1]-2,5-dimethyl-piperidine-3-carboxamide 1-53
Example 2: 1H-Pyrazol-4-y1-4-12-16-(trifluoromethyl)imidazo11,2-alpyridin-3-
yllpyrimidin-
4-yllmorpholine and 1H-pyrazol-4-y1-4-12-16-(trifluoromethyl)imidazo11,2-
alpyridin-3-
yllpyrimidin-4-yllmorpholine, 1-2 and 1-3
single single
N N enantiomer
N enantiomer
N1/NN NNN
N N N
F F F
F F HN ¨N F F FIN ¨N F F HN ¨N
1-2 1-3
[00432] The racemic mixture of 2-(1H-pyrazol-4-y1)-44246-
(trifluoromethyl)imidazo[1,2-
c]pyridin-3-yl]pyrimidin-4-yl]morpholine (prepared using a methodology similar
to the one
described in Example 107) was separated by chiral supercritical fluid
chromatography (conditions:
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OD-H, 45% Me0H, 20 mM NH3, 290 nm). The first species to be eluted was
compound 1-2
(99.3% ee); ESV-MS m/z 416.8 (M+H). The second specied to be eluted was
compound 1-3
(98.2% ee); ESV-MS m/z 416.4 (M+H).
[00433] The following compounds were prepared using a similar methodology to
the one
described in Example 2:
7-(2-(6-(Trifluoromethypimidazo[1,2-c]pyridin-3-yl)pyrimidin-4-
yl)hexahydroimidazo[1,5-
a] pyrazin-3(21/)-one 1-5
7-(2-(6-(trifluoromethyl)imidazo[1,2-c]pyridin-3-yl)pyrimidin-4-
y1)hexahydroimidazo[1,5-
a] pyrazin-3(21/)-one, 1-6
2-(1H-Pyrazol-4-y1)-4-(4-(6-(trifluoromethyl)imidazo[1,2-c]pyridin-3-
y1)pyrimidin-2-
y1)morpholine, 1-9
2-(1H-pyrazol-4-y1)-4-(4-(6-(trifluoromethypimidazo[1,2-c]pyridin-3-
y1)pyrimidin-2-
y1)morpholine, 1-10
Dimethyl((5-methy1-1-(2-(6-(trifluoromethyl)imidazo[1,2-c]pyridin-3-
y1)pyrimidin-4-
yl)piperidin-3-yl)iminoW-sulfanone 1-31 and dimethyl((5-methy1-1-(2-(6-
(trifluoromethyl)imidazo[1,2-c]pyridin-3-y1)pyrimidin-4-y1)piperidin-3-
ypimino)-k6-
sulfanone 1-32
34242,5-Dimethy1-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-4-y1]-6-
(trifluoromethyl)imidazo[1,2-a]pyridine 1-33 and 34242,5-dimethy1-3-(1H-
pyrazol-4-
yl)piperazin-1-yl]pyrimidin-4-y1]-6-(trifluoromethyl)imidazo[1,2-c]pyridine 1-
34
6-Chloro-34442,5-dimethy1-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-
yl]imidazo[1,2-
a]pyridine 1-35 and 6-chloro-34442,5-dimethy1-3-(1H-pyrazol-4-yl)piperazin-1-
yl]pyrimidin-2-yl]imidazo[1,2-c]pyridine 1-36
34442,5-Dimethy1-3-(1H-pyrazol-4-yl)piperazin-1 -yl]pyrimidin-2-y1]-6-
(trifluoromethyl)imidazo[1,2-a]pyridine 1-37 and 34442,5-dimethy1-3-(1H-
pyrazol-4-
yl)piperazin-1 -yl]pyrimidin-2-y1]-6-(trifluoromethyl)imidazo[1,2-a]pyridine 1-
38
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3 4443 -Methyl-5-(1H-pyrazol-4-y1)piperazin-1-yl]pyrimi din-2-yl] -6-
(trifluoromethyl)imi dazo[1,2-a]pyri dine 1-39 and 3-[443-methyl-5-(1H-pyrazol-
4-
yl)piperazin-1-yl]pyrimidin-2-y1]-6-(trifluoromethyl)imidazo[ 1,2-c]pyri dine
1-40
Example 3: N-I1(2S)-4-1246-(Difluoromethyl)imidazo[1,2-a]pyridin-3-
yllpyrimidin-4-
yllmorpholin-2-yllmethyllmethanesulfonamide, 1-13
9Iõo
No
[00434] DBU (79.8 tL, 0.534 mmol) and PyBroP (124.5 mg, 0.267 mmol) were added
to a
solution of 2[6-(difluoromethyl)imidazo[1,2-c]pyridin-3-yl]pyrimidin-4-ol (35
mg, 0.134 mmol)
in MeCN (700 After 5 min N-[[(2S)-morpholin-2-yl]methyl]methanesulfonamide
(31.1 mg,
0.160 mmol) was added and the mixture heated at 40 C. After 2 hours the
reaction was cooled to
room temperature and the mixture was filtered and purified by reverse phase
chromatography
(C18; MeCN/water/0.05% TFA as eluent) to afford the trifluoroacetic acid salt
of N-[[(2S)-4-[2-
[6-(difluoromethyl)imi dazo[1,2-c]pyri din-3 -yl]pyrimi din-4-yl]morpholin-2-
yl]methyl]methanesul fonami de (28.2 mg, 45%).
[00435] The following compounds were prepared using a methodology similar to
the one
described in Example 3:
N-[[(2S)-4-[246-(Trifluoromethyl)imidazo[1,2-c]pyridin-3-yl]pyrimidin-4-
yl]morpholin-2-
yl]methyl]methanesulfonamide, I-1 (using 2-[6-(trifluoromethyl)imidazo[1,2-
c]pyridin-3-
y1]-1H-pyrimidin-6-one)
144-[246-(Difluoromethypimidazo[1,2-c]pyridin-3-yl]pyrimidin-4-yl]piperazin-1-
yl]ethanone,
1-14
4-[2- [6-(Difluoromethyl)imidazo[1,2-c]pyridin-3 -yl]pyrimidin-4-y1]-2-(1H-
pyrazol-4-
yl)morpholine, 1-15
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N4(3S,5S)-1-(2-(6-(Difluoromethyl)imidazo[1,2-c]pyridin-3 -yl)pyrimidin-4-y1)-
4,4-difluoro-5-
m ethylpip eri din-3 -yl)m ethyl)m ethanesulfonami de, 1-16
2-(1H-Pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imi dazo [1,2-a] pyri din-3 -
yl)pyrimi din-4-
yl)morpholine, 1-45
Example 4:
N-I1(2S)-4-1446-(Difluoromethyl)imidazo[1,2-a]pyridin-3-Apyrimidin-2-
yllmorpholin-2-yllmethyllmethanesulfonamide, 1-17
N
9
H 0
[00436]
3-Bromo-6-(difluoromethyl)imidazo[1,2-c]pyridine (70 mg, 0.283 mmol), tributyl-
(2-
chloropyrimidin-4-yl)stannane (137.3 mg, 0.340 mmol) and PdC12(PPh3)2 (59.7
mg, 0.085 mmol)
were combined in DMF (2.1 mL) and degassed with nitrogen before heating at 120
C. To the
mixture was added N-[[(2S)-morpholin-2-yl]methyl]methanesulfonamide (27.7 mg,
0.143 mmol)
and diisopropylethylamine (49.6 tL, 0.285 mmol) and the reaction was heated at
150 C. After 16
hours the reaction was cooled to room temperature and the mixture was filtered
and purified by
reverse phase chromatography (C18; MeCN/water/0.05% TFA as eluent) to afford
the
trifluoroacetic acid salt of N-R2S)-44446-(difluoromethyl)imidazo[1,2-
c]pyridin-3-
yl]pyrimidin-2-yl]morpholin-2-yl]methyl]methanesulfonamide (6.5 mg, 5%).
[00437] The following compound was prepared using a methodology similar to the
one
described in Example 4:
4-[4-[6-(Difluoromethyl)imidazo[1,2-c]pyridin-3-yl]pyrimidin-2-y1]-2-(1H-
pyrazol-4-
yl)morpholine, 1-18
Example 5: 1-14-16-16-(Trifluoromethyl)imidazo11,2-alpyridin-3-y11-2-
pyridyllpiperazin-1-
yllethanone, I-11
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N N N\---(a I X
(i) Suzuki (ii) TFA
tN
" N
-N1)Th
0 (iii) AcCI
)K 0
F F F F
F F
Step 1: tert-Butyl 4-16-16-(trifluoromethyl)imidazo 11,2-al pyridin-3-y11-2-
pyridyll piperazine-
1-carboxylate
N N IN\
0)c.
0
F F
[00438] A mixture of 3-iodo-6-(trifluoromethyl)imidazo[1,2-c]pyridine (50 mg,
0.160 mmol),
tert-butyl-4- [6-(4,4,5,5-tetram ethyl-1,3 ,2-di ox ab orol an-2-y1)-2 -pyri
dyl] pip erazine-l-carb oxyl ate
(62.4 mg, 0.160 mmol), dppf (8.8 mg, 0.016 mmol), Pd(OAc)2 (1.8 mg, 0.008
mmol), CuCl (15.9
mg, 0.160 mmol) and Cs2CO3 (156.6 mg, 0.481 mmol) in DMF (1 mL) was degassed
with nitrogen
and heated to 90 C for 16 hours. The reaction was cooled to ambient
temperature, filtered through
a silica gel pad and concentrated under reduced pressure to afford tert-butyl
44646-
(trifluoromethypimidazo[1,2-c]pyridin-3 -yl] -2-pyridyl]piperazine-1-
carboxylate; ESV-MS m/z
448.2 (M+H). The material was used without further purification.
Step 2: 3-(6-Piperazin-1-y1-2-pyridy1)-6-(trifluoromethyl)imidazo[1,2-a]
pyridine
N
NH
F F
[00439] tert-Butyl-4[646-(trifluoromethyl)imi dazo[1,2-c]pyridin-3-y1]-2-
pyridyl]piperazine-
1-carboxylate was dissolved in DCM (2 mL) and TFA (1 mL, 12.98 mmol) was
added. The
mixture was stirred for 1 hour and then concentrated under reduced pressure.
The residue was
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dissolved in methanol and purified by means of an ion exchange SCX-2 cartridge
to afford 3-(6-
piperazin-1-y1-2-pyridy1)-6-(trifluoromethyl)imidazo[1,2-c]pyridine; ESV-MS
m/z 348.1 (M+H).
Step 3: 1-14-1646-(Trifluoromethyl)imidazo[1,2-a]pyridin-3-y11-2-
pyridyllpiperazin-1-
yllethanone
N
%
0
F F
[00440] Acetyl chloride (15 tL, 0.208 mmol) and triethylamine (67 tL, 0.481
mmol) were
added to a solution of 3-(6-piperazin-1-y1-2-pyridy1)-6-
(trifluoromethyl)imidazo[1,2-c]pyridine in
CH2C12 (1 mL) and stirred for 20 mins. The mixture was concentrated and
purified by reverse
phase chromatography (C18; MeCN/water/0.05% TFA as eluent) to afford the
trifluoroacetic acid
salt of 1444646-(trifluoromethyl)imidazo[1,2-c]pyridin-3-y1]-2-
pyridyl]piperazin-1-yl]ethanone
(5.5 mg, 5%).
Example 6: 2-(1H-Pyrazol-4-y1)-4-16-16-(trifluoromethyl)imidazo11,2-alpyridin-
3-y11-2-
pyridyllmorpholine, 1-12
N kr- NH
F F
[00441] 3-Bromo-6-(trifluoromethyl)imidazo[1,2-c]pyridine (100 mg, 0.377
mmol), 2-fluoro-
6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)pyridine (84.2 mg, 0.377 mmol),
dppf (20.6 mg,
0.038 mmol), Pd(OAc)2 (4.2 mg, 0.0189 mmol), CuCl (37.4 mg, 0.377 mmol) and
Cs2CO3 (368.8
mg, 1.132 mmol) in DMF (2 mL) were degassed with nitrogen and heated to 90 C
for 16 hours.
The reaction was cooled to ambient temperature and filtered through a silica
gel pad.
Diisopropylethylamine (48.8 mg, 66 tL, 0.377 mmol) and 2-(1H-pyrazol-4-
yl)morpholine (57.8
mg, 0.377 mmol) were added directly to the filtrate and the mixture was heated
at 120 C for 16
hours. The reaction mixture was cooled to ambient temperature, filtered and
purified by reverse
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phase chromatography (C18; MeCN/water/0.05% TFA as eluent) to afford the
trifluoroacetic acid
salt of 241H-pyrazol-4-y1)-44646-(trifluoromethyl)imi dazo[1,2-c]pyri
din-3 -yl] -2-
pyridyl]morpholine (3.1 mg, 2%).
Example 7: 4-14-(6-Chloroimidazo11,2-alpyridin-3-y1)-1,3,5-triazin-2-y11-2-(1H-
pyrazol-4-
yl)morpholine, 1-22
NN
Nr-"N NN
N CI
Jt
_________________________________ Et0/*QeLN--)____C.,--NH
N N H
Nr'N---NNH
GI Nr'CI / \-0
CI
Step 1: 4-(4-Chloro-1,3,5-triazin-2-y1)-2-(1H-pyrazol-4-yl)morpholine
NN
N.----N--NrCivH
[00442] To a solution of 2,4-dichloro-1,3,5-triazine (50 mg, 0.333 mmol) and
diisopropylethylamine (128 tL, 0.734 mmol) in 1,4-dioxane (500 ilt) was added
2-(1H-pyrazol-
4-yl)morpholine (51.1 mg, 0.333 mmol). The reaction mixture was stirred for 90
mins and then
was partitioned between DCM and water, the organics extracted, dried (MgSO4),
filtered and
concentrated to afford 4-(4-chloro-1,3,5-triazin-2-y1)-241H-pyrazol-4-
yl)morpholine; ESV-MS
m/z 267.1 (M+H). The material was used without further purification.
Step 2: 4-14-1(E)-2-Ethoxyviny11-1,3,5-triazin-2-y11-2-(1H-pyrazol-4-
yl)morpholine
N
Et0
[00443] 4(4-Chloro-1,3,5-triazin-2-y1)-241H-pyrazol-4-y1)morpholine was
dissolved in DME
(750 ilt) and 2(2-ethoxyviny1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (99 mg,
0.5 mmol) and
Na2CO3 (500 [IL of 2M, 1 mmol) were added. The mixture was degassed via
vacuum/nitrogen
cycles (x 3), then Pd(PPh3)4 (38.5 mg, 0.033 mmol) was added and the mixture
again degassed via
vacuum/nitrogen cycles (x 3). The mixture was heated at 40 C for 2 hours. The
reaction was
purified by column chromatography (silica, Et0Ac/Petroleum ether gradient) to
afford 444-[(E)-
2-ethoxyviny1]-1,3,5-triazin-2-y1]-241H-pyrazol-4-y1)morpholine; ESV-MS m/z
303.2 (M+H).
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Step 3: 4-14-(6-Chloroimidazo11,2-a]pyridin-3-y1)-1,3,5-triazin-2-y11-2-(1H-
pyrazol-4-
yl)morpholine
N"--
i N
N/-----k N-.:--
)\¨N nC-1 H
\--0
CI
[00444] NBS (5.9 mg, 0.033 mmol) was added to a solution of 444-[(E)-2-
ethoxyviny1]-1,3,5-
triazin-2-y1]-2-(1H-pyrazol-4-yl)morpholine (10 mg, 0.033 mmol) in 1,4-dioxane
(300 ilt) / water
(100 ilt) and the reaction mixture stirred for 15 minutes. 5-Chloropyridin-2-
amine (5.1 mg, 0.040
mmol) was then added and the reaction mixture heated at 65 C. After 16 hours
the reaction
mixture was cooled to ambient temperature, filtered and purified by reverse
phase chromatography
(C18; MeCN/water/0.05% TFA as eluent) to afford the trifluoroacetic acid salt
of 44446-
chl oroimi dazo[1,2-a] pyri din-3 -y1)-1,3, 5-triazin-2-yl] -2 -(1H-pyrazol-4-
yl)m orpholine (4.9 mg,
26%).
Example 8: ((1-(2-(6-Chloroimidazo11,2-alpyridin-3-yl)pyrimidin-4-y1)-2,5-
dimethylpiperidin-3-yl)methyl)(imino)(methyl)-X6-sulfanone (trans
diastereomer), 1-46
N--
N-----
NN----2CI + \ ,N
DIPEA, NMP .... N \/--/N N-11\ N C'S--- Ph1(0Ac)2 )LN
N \
\
\ N
\ /
GI ci
Step 1: 6-Chloro-3-14-12,5-dimethy1-3-(methylsulfinylmethyl)-1-
piperidyllpyrimidin-2-
yllimidazo[1,2-alpyridine (trans diastereomer)
o
---
)\¨N - N
CI
[00445] A microwave vial was charged with 6-chloro-3-(4-chloropyrimidin-2-
yl)imidazo[1,2-
c]pyridine (30 mg, 0.113 mmol), 2,5-dimethy1-3-
(methylsulfinylmethyl)piperidine
(dihydrochloride salt) (42 mg, 0.160 mmol) , DIPEA (60 l.L, 0.345 mmol) and
NMP (900 ilt)
before sealing and heating at 100 C for 16 hours. The reaction was allowed to
cool before
purifying by reverse phase chromatography (C18; MeCN / water ¨ 0.1% ammonium
hydroxide as
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eluent) to provide 6-chl oro-3
[2,5 -dim ethy1-3 -(m ethyl sulfinylm ethyl)-1-pip eri dyl] pyrimidin-
2-yl]imidazo[1,2-c]pyridine (11 mg, 45%).
Step 2: ((1-(2-(6-Chloroimidazo11,2-al pyridin-3-yl)pyrimidin-4-y1)-2,5-
dimethylpiperidin-3-
yl)methyl)(imino)(methyl)- X6-sulfanone (trans diastereomer)
HN
N'\\&J.\jSO
)\¨N N
CI
[00446] Methanol (375 L) was added to a mixture of 6-chloro-34442,5-dimethy1-
3-
(methyl sul finylmethyl)-1 -piperidyl]pyrimidin-2-yl]imidazo[1,2-a]pyridine
(11.2 mg, 0.144
mmol) and (diacetoxyiodo)benzene (34.7 mg, 0.108 mmol) followed by DCM (375
L). The
reaction was stirred at ambient temperature for 3 hours. The crude reaction
mixture was filtered
then purified by reverse phase chromatography (C18; MeCN / water ¨ 0.1%
ammonium hydroxide
as eluent) to give
((1-(2-(6-chloroimidazo[1,2-c]pyridin-3-yl)pyrimidin-4-y1)-2,5-
dimethylpiperidin-3-y1)methyl)(imino)(methyl)- AP-sulfanone (3mg, 19%, trans
diastereomer) I-
46.
[00447] The following compound was prepared using a methodology similar to the
one
described in Example 8:
((1-(2-(6-Chloroimidazo[1,2-c]pyridin-3-yl)pyrimidin-4-y1)-2,5-
dimethylpiperidin-3-
y1)methyl)(imino)(methyl)- X6-sulfanone (cis diastereomer), 1-47
Example 9: 6-chloro-3-{4-cis-2-methyl-6-(3-methyl-11,2,410xad1az01-5-y1)-
morpholin-4-yll-
pyrimidin-2-yl}-imidazo[1,2-alpyridine, 1-54
x
N
N
+ ,\N DIPEA, ACN, N1 )ri\N NTh.,okio,\N
0
CI
CI
[00448]
To a microwave vial containing 6-chloro-3-(4-chloro-pyrimidin-2-y1)-
imidazo[1,2-
c]pyridine (50.00 mg; 0.19 mmol; 1.00 eq.) and rac-(2r,60-2-methy1-6-(3-methy1-
1,2,4-oxadiazol-
5-yl)morpholine hydrochloride (41.43 mg; 0.19 mmol; 1.00 eq.) was added DIPEA
(0.11 ml; 0.66
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mmol; 3.50 eq.) and acetonitrile (2.00 m1). The reaction was stirred at 85 C
for 2h before the
mixture was diluted in 5 mL DMSO (partially dissolved), filtered and purified
with basic pre-
HPLC (C18,10-90% ACN/H20/0.1% NH4OH as eluent) to afford the 6-chloro-3-{4-cis-
2-methy1-
6-(3-methy141,2,4]oxadiazol-5-y1)-morpholin-4-y1]-pyrimidin-2-y1}-imidazo[1,2-
c]pyridine (5.0
mg, 6.4%)
[00449] The following compounds were prepared using a methodology similar to
the one
described in Example 9:
6-Chloro-3-{443-(1H-imidazol-4-y1)-piperidin-1-y1]-pyrimidin-2-y1} -
imidazo[1,2-c]pyridine, I-
3-(2-((3R,5R)-3-Methy1-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-136 (after chiral separation)
3-(2-((3 S,5S)-3-Methy1-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-137 (after chiral separation)
5-Methyl-142-(6-trifluorom ethyl-imi dazo [1,2-a] pyri din-3 -y1)-pyrimi din-4-
yl] -pip eri dine-3 -
carb oxylic acid amide, 1-149
(S)-142-(6-Trifluoromethyl-imidazo[1,2-a] pyridin-3-y1)-pyrimidin-4-y1]-
piperidine-3-
carboxylic acid amide, 1-154
5,5-Difluoro-142-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-y1)-pyrimidin-4-
y1]-piperidine-3-
carboxylic acid methyl ester, 1-570
[00450] 2- [(3R,5R)-3 -methy1-5-(1H-pyrazol-4-yl)piperidin-1-y1]-446-
(trifluoromethypimidazo[1,2-a]pyridin-3 -yl]pyrimidine 1-136 and 3 -(2-((3 S,5
S)-3 -Methyl-5 -(1H-
pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-y1)-6-(trifluoromethyl)imidazo[1,2-
a]pyridine, 1-137
were purified by Prep-Chiral-HPLC at follows:
[00451] (2-[(3R,5R)-3-methy1-5-(1H-pyrazol-4-yl)piperidin-1-y1]-446-
(trifluoromethypimidazo[1,2-a]pyridin-3-yl]pyrimidine (200 mg, 0.42 mmol, 1
equiv, 90%) was
purified by Prep-Chiral-HPLC with the following conditions (Column: Chiralpak
IA, 2*25cm,
5um;Mobile Phase A:Hex(8mmo1/L NH3.Me0H)--HPLC, Mobile Phase B: IPA--HPLC;
Flow
rate: 20 mL/min; Gradient: 20 B to 20 B in 25 min; 254/220 nm; RT1:11.829).
This resulted in
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116.2 mg (63.86%) of 2-[(3R,5R)-3-methy1-5-(1H-pyrazol-4-
yl)piperidin- 1 -y1]-446-
(trifluoromethypimidazo[1,2-a]pyridin-3-yl]pyrimidine 1-136 as a white solid.
[00452] 2-[(3S,5S)-3-methy1-5-(1H-pyrazol-4-yl)piperidin- 1 -y1]-446-
(trifluoromethypimidazo[1,2-a]pyridin-3-yl]pyrimidine 200 mg, 0.42 mmol, 1
equiv, 90%) was
purified by Prep-Chiral-HPLC with the following conditions (Column: Chiralpak
IA, 2*25cm,
5um;Mobile Phase A:Hex(8mmo1/L NH3.Me0H)--HPLC, Mobile Phase B: IPA--HPLC;
Flow
rate: 20 mL/min; Gradient: 20 B to 20 B in 25 min; 254/220 nm; RT2:19.149).
This resulted in
117.8 mg of 2-[(3S,5S)-3-methy1-5-(1H-pyrazol-4-yl)piperidin-1-
y1]-446-
(trifluoromethypimidazo[1,2-a]pyridin-3-yl]pyrimidine 1-137 as a white solid
Example 10: 6-Chloro-7-fluoro-3-{4-Icis-2-methyl-6-(3-methyl-11,2,41oxadiazol-
5-y1)-
morpholin-4-yll-pyrimidin-2-yl}-imidazo11,2-a]pyridine, 1-56
+N( H A DIPEA,
CI 0
F CI
F CI
[00453] To a microwave vial containing 6-chloro-3-(4-chloro-pyrimidin-2-y1)-7-
fluoro-
imidazo[1,2-c]pyridine (50.00 mg; 0.18 mmol; 1.00 eq.) and rac-(2r,60-2-methy1-
6-(3-methy1-
1,2,4-oxadiazol-5-y1) morpholine hydrochloride (38.80 mg; 0.18 mmol; 1.00 eq.)
was added
DIPEA (0.10 ml; 0.62 mmol; 3.50 eq.) and acetonitrile (2.00 m1). The reaction
was stirred at 85 C
for 2h. The white precipitate was filtered, wash with H20 (2 mL X 2), dried to
afford 6-chloro-7-
fluoro-3-{4-[cis-2-methyl-6-(3-methyl-[1,2,4]oxadiazol-5-y1)-morpholin-4-y1]-
pyrimidin-2-y1}-
imidazo[1,2-c]pyridine (75.9mg, 79.2%).
[00454] The following compounds were prepared using a methodology similar to
the one
described in Example 10:
6-Chloro-7-fluoro-3-{443-(1H-imidazol-4-y1)-piperidin-1-y1]-pyrimidin-2-y1}-
imidazo[1,2-
c]pyridine, 1-57
3-{4-[(3 S,5 S)-3-Methyl-5-(1-methyl-1H-pyrazol-4-y1)-piperidin-1-y1]-
pyrimidin-2-y1} -6-
trifluoromethyl-imidazo[1,2-c]pyridine (racemic mixture), 1-60
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3-{4-[(3R,5S)-3-Methy1-5-(1-methyl-1H-pyrazol-4-y1)-piperidin-1-y1]-pyrimidin-
2-y1}-6-
trifluoromethyl-imidazo[1,2-c]pyridine (racemic mixture), 1-61
142-(6-Chloro-imidazo[1,2-c]pyridin-3-y1)-pyrimidin-4-y1]-3-(3-
methy141,2,4]oxadiazol-5-y1)-
pyrrolidin-3-ol, 1-64
6-Chloro-344-(3-isoxazol-4-yl-piperidin-1-y1)-pyrimidin-2-y1]-imidazo[1,2-
c]pyridine, 1-65
6-Chloro-344-(3-isoxazol-3-yl-piperidin-1-y1)-pyrimidin-2-y1]-imidazo[1,2-
c]pyridine, 1-66
342-(6-Chloro-imidazo[1,2-c]pyridin-3-y1)-pyrimidin-4-y1]-3-aza-
bicyclo[4.1.0]heptan-6-ol, I-
67
4-{ 142-(6-Chloro-imidazo[ 1,2-c]pyridin-3 -y1)-pyrimidin-4-y1]-piperidin-3 -
y1} -4-methyl-
oxazolidin-2-one, 1-68
1-Methy1-442-(6-trifluoromethyl-imidazo[1,2-c]pyridin-3-y1)-pyrimidin-4-y1]-
[1,4]diazepan-2-
one, 1-69
3-{4-[(3aR,6aR)-3a-(3-Isopropyl-[1,2,4]oxadiazol-5-y1)-hexahydro-
cyclopenta[c]pyrrol-2-y1]-
pyrimidin-2-y1}-6-trifluoromethyl-imidazo[1,2-a]pyridine, 1-70
344-(3-Methyl-piperidin-1-y1)-pyrimidin-2-y1]-6-trifluoromethyl-imidazo[1,2-
c]pyridine, 1-71
142-(6-Chloro-imidazo[1,2-c]pyridin-3-y1)-pyrimidin-4-y1]-3-(1-isopropy1-1H-
[1,2,3]triazol-4-
y1)-pyrrolidin-3-ol, 1-72
6-Chloro-3-{4-[(2S,3S)-2-(3-chloro-pheny1)-3-methyl-morpholin-4-y1]-pyrimidin-
2-y1}-7-
fluoro-imidazo[1,2-c]pyridine (racemic mixture), 1-73
342-(6-Trifluoromethyl-imidazo[1,2-c]pyridin-3-y1)-pyrimidin-4-y1]-3-aza-
bicyclo[4.1.0]heptan-l-ol, 1-74
6-Chloro-3-{4-[(3aR,6aR)-3a-(3-isopropyl-[1,2,4]oxadiazol-5-y1)-hexahydro-
cyclopenta[c]pyrrol-2-y1]-pyrimidin-2-y1}-imidazo[1,2-a]pyridine (racemic
mixture), I-
142-(6-Chloro-imidazo[1,2-c]pyridin-3-y1)-pyrimidin-4-y1]-3-(1-isopropy1-1H-
[1,2,3]triazol-4-
y1)-piperidin-3-ol, 1-76
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(S)-142-(6-Chloro-7-fluoro-imidazo[1,2-c]pyridin-3-y1)-pyrimidin-4-y1]-
piperidine-3-carboxylic
acid (1-methyl-1H-pyrazol-4-y1)-amide, 1-77
542-(6-Chloro-imidazo[1,2-c]pyridin-3-y1)-pyrimidin-4-y1]-5-aza-
spiro[2.5]octane-1-carboxylic
acid, 1-78
6-Chloro-344-(7,7-difluoro-6-methy1-3-aza-bicyclo[4.1.0]hept-3-y1)-pyrimidin-2-
y1]-
imidazo[1,2-c]pyridine, 1-79
442-(6-Trifluoromethyl-imidazo[1,2-c]pyridin-3-y1)-pyrimidin-4-y1]-
[1,4]diazepan-2-one, 1-80
142-(6-Chloro-7-fluoro-imidazo[1,2-c]pyridin-3-y1)-pyrimidin-4-y1]-3-phenyl-
piperidin-3-ol, I-
81
1-1142-(6-Chloro-imidazo[1,2-c]pyridin-3-y1)-pyrimidin-4-y1]-3-hydroxy-
piperidin-3-y1}-
cyclobutanecarboxylic acid methyl ester, 1-82
1-[2-(6-Chloro-7-fluoro-imidazo[1,2-c]pyridin-3 -y1)-pyrimidin-4-y1]-3-phenyl-
piperidin-4-y1}-
methanol, 1-83
6-Chloro-344-(1-pheny1-3-aza-bicyclo[3.1.0]hex-3-y1)-pyrimidin-2-y1]-
imidazo[1,2-a]pyridine,
1-84
{ 1-[2-(6-Chloro-7-fluoro-imidazo[1,2-c]pyridin-3 -y1)-pyrimidin-4-y1]-3-
phenyl-piperidin-3-ylI-
methanol, 1-85
Example 11: (8)-142-(6-Chloro-7-fluoro-imidazo[1,2-alpyridine-3-y1)-pyrimidin-
4-y11-
piperidine-3-carboxylic acid, 1-58
0 0 N
+ NH2 I
N HN TEA, ACN N TEA, T3P 0-
.011\NH
CI
F CI I-IN-N
F CI
I-IN-N
F CI
Step 1: (S)-142-(6-Chloro-7-fluoro-imidazo 11,2-alpyridine-3-y1)-pyrimidin-4-
y11-piperidine-
3-carboxylic acid
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"r4NA
r_sl "kOH
F CI
[00455] To a solution of 6-Chloro-3-(4-chloro-pyrimidin-2-y1)-7-fluoro-
imidazo[1,2-
c]pyridine (120.00 mg; 0.42 mmol; 1.00 eq.) and (R)-(-)-nipecotic acid (54.75
mg; 0.42 mmol;
1.00 eq.) in acetonitrile (2.00 ml) was added TEA (0.15 ml; 1.06 mmol; 2.50
eq.) and allowed to
stir at 85 C for 3h. The white precipitate was dried and used in the next
step.
Step 2: (S)-142-(6-Chloro-7-fluoro-imidazo11,2-alpyridine-3-y1)-pyrimidin-4-
yll-piperidine-
3-carboxylic acid (1H-pyrazol-4-y1)-amide
0=41(NH
F CI HN¨N
[00456] To a rbf containing (S)-142-(6-Chloro-7-fluoro-imidazo[1,2-c]pyridine-
3-y1)-
pyrimidin-4-y1]-piperidine-3-carboxylic acid (50.00 mg; 0.10 mmol; 1.00 eq.)
and 1H-Pyrazol-4-
ylamine (8.27 mg; 0.10 mmol; 1.00 eq.) in DCM (2.00 ml) was added TEA (0.03
ml; 0.22 mmol;
2.20 eq.). After stirring at rt for 2 min, 1-propanephosphonic anhydride
(63.37 mg; 0.20 mmol;
2.00 eq.) was added in two portions. The reaction was stirred at rt for 15 min
before it was
concentrated, diluted with 2 mL Me0H/1mL DMSO, filtered and purified with
basic pre-HPLC
(10-90% 1/H20/0.1% NH4OH as eluent) to afford (S)-1-[2-(6-Chloro-7-fluoro-
imidazo[1,2-
c]pyridine-3-y1)-pyrimidin-4-y1]-piperidine-3-carboxylic acid (1H-pyrazol-4-
y1)-amide (43.9 mg,
15.6%).
[00457] The following compounds were prepared using a methodology similar to
the one
described in Example 11:
(S)-142-(6-Chloro-7-fluoro-imidazo[1,2-c]pyridine-3-y1)-pyrimidin-4-y1]-
piperidine-3-
carboxylic acid (1-methyl-1H-pyrazol-4-y1)-amide, 1-59
(S)-142-(6-Chloro-7-fluoro-imidazo[1,2-c]pyridine-3-y1)-pyrimidin-4-y1]-
piperidine-3-
carboxylic acid pyridine-4-ylamide, 1-86
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Example 12: (3S)-1-(2-{6-chloroimidazo[1,2-a]
amine, 1-87
r,
I O
Nr CI NH
NN N
SNAr HCI N N 'NH2
CI CI
CI
Step 1: tert-butyl N-1(3S)-1-(2-{6-chloroimidazo [1,2-a] pyridine-3-
yl}pyrimidin-4-
yl)piperidin-3-y1] carbamate
0
ci
[00458] A mixture of tert-butyl N-[(3S)-piperidin-3-yl]carbamate (195.3 mg,
0.98 mmol) and
6-chloro-3-(4-chloro-pyrimidin-2-yl)imidazo[1,2-c]pyridine (198.8 mg, 0.75
mmol) in DCM
(3.75 mL) was added triethylamine (0.21 mL, 1.50 mmol). After stirring
overnight at room
temperature reaction quenched with water (3 mL) and extracted with DCM (2 x 5
mL). The
combined organic layers were dried over anhydrous sodium sulfate, filtered and
solvent removed
in vacuo to afford tert-butyl N-[(3 S)-1-(2- { 6-chl oroimi daz o [1,2-a] pyri
dine-3 -yl}pyrimi din-4-
yl)piperidin-3-yl]carbamate; ESI-MS m/z 429.2 (M+H). The material was used
withour further
purification.
Step 2: (3S)-1-(2-{6-chloroimidazo[1,2-alpyridine-3-yl}pyrimidin-4-
yl)piperidin-3-amine
N
\
CI
[00459] N-[(3 S)-1-(2- { 6-chloroimidazo[1,2-c]pyridine-3-yl}pyrimidin-4-
y1)piperi din-3-
yl]carbamate was dissolved in 1,4-dioxane (3 mL) and 4H HC1 in 1,4-dioxane (3
mL, 35.2 mmol)
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was added. The mixture was stirred for 1 hour at 40 C and then concentrated
under reduced
pressure. The residue was dissolved in DMSO and purified by reverse phase
chromatography
(C18; MeCN/water/0.01% NH4OH as eluent) to afford (3S)-1-(2-{6-
chloroimidazo[1,2-
c]pyridine-3-yl}pyrimidin-4-yl)piperidin-3-amine (72.7 mg, 29%).
Example 13: 6-Chloro-7-fluoro-3-14-(2-pyridin-2-yl-morpholin-4-y1)-pyrimidin-2-
y11-
imidazo11,2-al pyridine, 1-88
N')õ, ,(C)
/y
N N
CI
[00460] 6-chloro-4-(4-chloro-pyrimidin-2-y;)-7-fluoro-imidazo[1,2-
c]pyridine (50.0 mg, 0.18
mmol), 2-(pyridine-2-yl)morpholine (35.0 mg, 0.21 mmol), triethylamine (20 tL,
0.18 mmol) in
DMF (1.0 mL) were heated at 80 C. After 14 hrs the reaction was cooled to
room temperature
and the mixture was filtered and purified by reverse phase chromatography
(C18;
MeCN/water/0.01% NH4OH as eluent) to afford 6-chloro-7-fluoro-3-[4-(2-pyridin-
2-yl-
morpholin-4-y1)-pyrimidin-2-y1]-imidazo[1,2-c]pyridine (11.1 mg, 16%).
[00461] The following compounds were prepared using a methodology similar to
the one
described in Example 13:
ci s-2-methy1-6-(5-methy1-1,3,4-oxadi azol-2-y1)-4- { 246-
(trifluoromethypimidazo[1,2-c]pyridin-
3 -yl]pyrimidin-4-y1 morpholine, 1-93 (using 3 -(4-Chl oropyrimidin-2-y1)-6-
(trifluoromethypimidazo[1,2-c]pyridine)
3- { 4- [ci s-2-methy1-6-(5-methy1-1,3,4-oxadiazol-2-y1)morpholin-4-
yl]pyrimidin-2-
yl imidazo[1,2-a]pyridine-6-carb onitrile, 1-94 (using 3 -(4-chloropyrimidin-2-
yl)imidazo[1,2-c]pyridine-6-carb onitrile)
cis-4-(2-{6-chloroimidazo[1,2-c]pyridin-3-yl}pyrimidin-4-y1)-2-methyl-6-(5-
methyl-1,3,4-
oxadiazol-2-y1)morpholine, 1-95 (using 4-chloro-2-{6-chloroimidazo[1,2-
c]pyridin-3-
yl}pyrimidine)
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2424 6-chloroimidazo[1,2-c]pyridin-3 -ylIpyrimidin-4-y1)-octahydro-1H-
pyrazino[1,2-
c]pyrimidin-6-one, 1-96 (using 4-chloro-2-{6-chloroimidazo[1,2-c]pyridin-3-
yl}pyrimidine)
7424 6-chloroimidazo[1,2-c]pyridin-3-ylIpyrimidin-4-y1)-octahydroimidazo[1,5-
a]pyrazin-3-
one, 1-97 (using 4-chloro-2-{6-chloroimidazo[1,2-c]pyridin-3-yl}pyrimidine)
2424 6-chloroimidazo[1,2-c]pyridin-3 -ylIpyrimidin-4-y1)-octahydropyrazino[1,2-
c] [1,3] oxazin-
6-one, 1-98 (using 4-chloro-2-{6-chloroimidazo[1,2-c]pyridin-3-yl}pyrimidine)
7424 6-chloroimidazo[1,2-c]pyridin-3 -ylIpyrimidin-4-y1)-hexahydro-1H-[1,3
oxazolo[3,4-
a]pyrazin-3-one, 1-99 (using 4-chloro-2-{6-chloroimidazo[1,2-c]pyridin-3-
yl}pyrimidine)
2- {6-chloroimidazo[1,2-c]pyridin-3-y1} -443-(1H-pyrazol-4-yl)piperidin-1-
yl]pyrimidine, 1-100
(using 4-chloro-2-{6-chloroimidazo[1,2-c]pyridin-3-yl}pyrimidine)
443-(1H-pyrazol-4-yl)piperidin-1-y1]-246-(trifluoromethyl)imidazo[1,2-
c]pyridin-3-
yl]pyrimidine, 1-101 (using 3-(4-Chloropyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[1,2-
c]pyridine)
Example 14:
2-methyl-6-(3-methyl-1,2,4-oxadiazo1-5-y1)-4-{2-16-
(trifluoromethyl)imidazo11,2-alpyridin-3-y11pyrimidin-4-yl}morpholine , 1-89
and 1-90
single diastereomer
single enantiomer single enantiomer
(pair of enantiomers)
O'N O'N O'N
N N
L
/Th\jr
L.(0 + N
CF3 CF3 CF3
1004621
The racemic mixture of cis- (2-methy1-6-(3-methy1-1,2,4-oxadiazol-5-y1)-4-{246-
(trifluoromethypimidazo[1,2-c]pyridin-3-yl]pyrimidin-4-ylImorpholine (prepared
using a
methodology similar to the one described in Example 1) was separated by chrial
supercritical fluid
chromatography (conditions: IA-H, Me0H + 0.5% DMEA, 2 mL/min, 220 nm). The
first species
to be eluted was compound 1-89 (98% ee); ESI-MS m/z 446.2 (M+H). The second
specied to be
eluted was compound 1-90 (98% ee); ESI-MS m/z 446.2 (M+H).
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[00463] The following compounds were prepared using a similar methodology to
the one
described in Example 14:
3-{4-[(2S,6S)-2-methy1-6-(3-methyl-1,2,4-oxadiazol-5-yl)morpholin-4-
yl]pyrimidin-2-
ylIimidazo[1,2-c]pyridine-6-carbonitrile, 1-91 and 3-{4-[(2R,6R)-2-methy1-6-(3-
methyl-
1,2,4-oxadiazol-5-yl)morpholin-4-yl]pyrimidin-2-ylIimidazo[1,2-c]pyridine-6-
carbonitrile, 1-92
Example 15: Exemplary Compounds 1-102 to 1-113.
[00464] Additional compounds were prepared using similar methodologies to
those described
in examples 1-14 above:
(S)-1-(2-(6-chloroimidazo[1,2-c]pyridin-3-yl)pyrimidin-4-y1)piperidine-3-
carboxamide, 1-102
N-(((3S,5S)-1-(3-(6-(difluoromethyl)imidazo[1,2-c]pyridin-3-y1)-1,2,4-
thiadiazol-5-y1)-4,4-
difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide, 1-103
2-(1H-pyrazol-4-y1)-4-(3-(6-(trifluoromethypimidazo[1,2-c]pyridin-3-y1)-1,2,4-
thiadiazol-5-
y1)morpholine, 1-104
4-(3-(6-(difluoromethyl)imidazo[1,2-c]pyridin-3-y1)-1,2,4-thiadiazol-5-y1)-2-
(1H-pyrazol-4-
yl)morpholine, 1-105
(S)-N-((4-(3-(6-(trifluoromethyl)imidazo[1,2-c]pyridin-3-y1)-1,2,4-thiadiazol-
5-yl)morpholin-2-
y1)methyl)methanesulfonamide, 1-106
(S)-N-((4-(3-(6-(difluoromethyl)imidazo[1,2-c]pyridin-3-y1)-1,2,4-thiadiazol-5-
yl)morpholin-2-
y1)methyl)methanesulfonamide, 1-107
2-(1H-pyrazol-4-y1)-4-(5-(6-(trifluoromethypimidazo[1,2-c]pyridin-3-y1)-1,2,4-
thiadiazol-3-
y1)morpholine, 1-108
(S)-N-((4-(5-(6-(trifluoromethyl)imidazo[1,2-c]pyridin-3-y1)-1,2,4-thiadiazol-
3-yl)morpholin-2-
y1)methyl)methanesulfonamide, 1-109
N4(1-(5-(6-(trifluoromethyl)imidazo[1,2-c]pyridin-3-y1)-1,2,4-thiadiazol-3-
y1)piperidin-3-
y1)methyl)methanesulfonamide, 1-110
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(S)-N-((4-(4-(6-(trifluoromethyl)imidazo[1,2-c]pyridin-3-yl)thiazol-2-
y1)morpholin-2-
y1)methyl)methanesulfonamide, I-111
N4(1-(3-(6-(trifluoromethyl)imidazo[1,2-c]pyridin-3-y1)-1,2,4-thiadiazol-5-
y1)piperidin-3-
y1)methyl)methanesulfonamide, 1-112
(S)-N-((4-(6-(6-chloroimidazo[1,2-c]pyridin-3-yl)pyrazin-2-y1)morpholin-2-
y1)methyl)methanesulfonamide, 1-113
Example 16: 6-chloro-3-{4-cis-2-methyl-6-(3-methyl-11,2,41oxadiazol-5-y1)-
morpholin-4-yll-
pyrimidin-2-yl}-imidazo[1,2-alpyridine, 1-114
CH CH
NO.,o N
CI +
%
CF3
CF3
[00465] To a 25-mL sealed tube, was placed 2-chloro-446-
(trifluoromethyl)imidazo[1,2-
c]pyridin-3-yl]pyrimidine (200.000 mg, 0.60 mmol, 1.00 equiv, 90%), 3-methy1-5-
(1H-pyrazol-
4-yl)piperidine (110.658 mg, 0.60 mmol, 1.00 equiv, 90%), DIEA (163.993 mg,
1.21 mmol, 2.00
equiv, 95%), i-propanol (10.000 mL, 124.30 mmol, 206.24 equiv, 95%). The
resulting solution
was stirred for overnight at 100 C. The resulting mixture was concentrated
under vacuum. The
crude product (300 mg) was purified by Prep-HPLC with the following conditions
(Prep-HPLC-
015): Column, )(Bridge Shield RP18 OBD Column, 30*150mm,5um; mobile phase,
Water(lOMMOL/L NH4HCO3+0.1%NH3.H20) and ACN (43.0% ACN up to 47.0% in 9 min);
Detector, uv 254nm. This resulted in 23.9 mg (9%) of 243-methy1-5-(1H-pyrazol-
4-yl)piperidin-
1-y1]-446-(trifluoromethyl)imidazo[1,2-c]pyridin-3-yl]pyrimidine 1-114 as a
white solid.
[00466] The following compounds were prepared using a methodology similar to
the one
described in Example 16:
cis-2-Methyl-6-(3-methyl-1H-pyrazol-4-y1)-4- { 4- [6-(trifluorom ethyl)imi
dazo [1,2-a] pyri din-3 -
yl]pyrimidin-2-y1} m orpholine, 1-115
cis-2-Methyl-6-(1H-pyrazol-4-y1)-4- { 4-[6-(trifluoromethyl)imi dazo [1,2-
c]pyri din-3 -
yl]pyrimidin-2-y1} m orpholine, 1-117
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3-{4-[cis-2-Methy1-6-(3-methy1-1H-pyrazol-4-y1)-morpholin-4-y1]-pyrimidin-2-
y1{-6-
trifluoromethyl-imidazo[1,2-c]pyridine, 1-119
Table 2: Analytical data for compounds of formula I
[00467] Purity and retention time of the compounds from this invention were
measured by
HPLC.
[00468] HPLC method: analytical reverse phase UPLC-MS was carried out on a
waters Acquity
UPLC-MS system equipped with a waters BEH 1.7mm C-18 reverse phase column (2.1
mm x 50
mm, 1.7 m). The mobile phases were acetonitrile and water/acetonitrile (95:5
with 10 mM
ammonium formate, pH 9). Run time 5 min
LCM
Cmpd LCMS
S (rt, NMR
No. (ES+)
mm)
(500 MHz, Methanol-d4) 6 10.40 (s, 1H), 8.71 (s, 1H), 8.34 (d,
I-1 457.2 2.46 1H), 8.03 (d, 1H), 7.93 (dd, 1H), 6.91 (d, 1H), 4.58
- 4.34 (m,
1H), 4.13 (ddd, 1H), 3.80 -3.68 (m, 2H), 3.22 - 3.12 (m, 1H),
2.99 (s, 3H)
(500 MHz, DMSO-d6) 6 10.33 (s, 1H), 8.65 (s, 1H), 8.42 (d, 1H),
1-2 416.8 2.37 7.99 (d, 1H), 7.75 (dd, 1H), 7.69 (s, 2H), 6.95 (d,
1H), 4.60 (dd,
1H), 4.08 - 4.01 (m, 1H), 3.23 (dd, 2H)
(500 MHz, DMSO-d6) 6 10.33 (s, 1H), 8.65 (s, 1H), 8.42 (d, 1H),
1-3 416.4 2.37 7.99 (d, 1H), 7.75 (dd, 1H), 7.69 (s, 2H), 6.95 (d,
1H), 4.60 (dd,
1H), 4.08 -4.01 (m, 1H), 3.23 (dd, J = 13.1, 10.6 Hz, 2H)
(500 MHz, DMSO-d6) 6 10.43 - 10.36 (m, 1H), 8.61 (d, 1H),
1-4 439.2 2.41 8.40 (dd, 1H), 7.97 (dt, 1H), 7.72 (dd, 1H), 6.79
(d, 1H), 3.90 -
3.66 (m, 2H), 3.62 (d, 3H), 3.37 - 3.08 (m, 2H), 2.36 (d, 1H), 2.02
(s, 1H), 1.79 (s, 1H), 1.68 - 1.47 (m, 2H)
(500 MHz, Methanol-d4) 6 10.38 - 10.32 (m, 1H), 8.75 (s, 1H),
1-5 404.5 2.24 8.34 (d, 1H), 8.04 (d, 1H), 7.94 (dd, 1H), 6.99 (d,
1H), 4.79 - 4.65
(m, 1H), 4.65 - 4.47 (m, 1H), 4.01 - 3.88 (m, 2H), 3.65 (dd, 1H),
3.29 - 3.17 (m, 3H), 3.12 (ddd, 1H)
(500 MHz, Methanol-d4) 6 10.38 - 10.32 (m, 1H), 8.75 (s, 1H),
1-6 404.4 2.24 8.34 (d, 1H), 8.04 (d, 1H), 7.94 (dd, 1H), 6.99 (d,
1H), 4.79 - 4.65
(m, 1H), 4.65 - 4.47 (m, 1H), 4.01 - 3.88 (m, 2H), 3.65 (dd, 1H),
3.29 - 3.17 (m, 3H), 3.12 (ddd, 1H)
(500 MHz, DMSO-d6) 6 10.47 (d, 1H), 8.47 (s, 1H), 8.36 (d,
1-7 481.2 3.13 1H), 7.96 (d, 1H), 7.70 (dd, 1H), 6.48 (s, 2H),
3.72¨ 3.65 (m,
6H), 2.95 (s, 3H), 2.88 (dd, 2H), 2.16 ¨2.08 (m, 2H), 1.96 (p,
2H), 1.51 (d, 2H)
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LCM
Cmpd LCMS
S (rt, '11 NMR
mm)
(400 MHz, d4-Me0H) 6 8.81 (d, 1H), 7.16 (d, 1H), 3.98 (dd,
1-8 398.1 1.47 1H), 3.76 (dt, 1H), 3.50 (dd, 1H), 3.35 (ddd, 1H),
2.68 (tt, 1H),
2.05 (dt, 1H), 1.88 - 1.58 (m, 3H)
(500 MHz, Methanol-d4) 6 10.50 (s, 1H), 8.56 (s, 1H), 8.44 (d,
1-9 416.1 2.39 1H), 7.89 (d, 1H), 7.73 (br s, 2H) 7.70 (dd, 1H),
7.26 (d, 1H),
4.74 - 4.70 (m, 2H), 4.58 (d, 1H), 4.13 (ddd, 1H), 3.87 (td, 1H),
3.37- 3.28 (m, 2H)
(500 MHz, Methanol-d4) 6 10.50 (s, 1H), 8.56 (s, 1H), 8.44 (d,
1-10 416.3 2.38 1H), 7.89 (d, 1H), 7.74 (br s, 2H), 7.70 (dd, 1H),
7.26 (d, 1H),
4.74 - 4.70 (m, 2H), 4.58 (d, 1H), 4.13 (ddd, 1H), 3.87 (td, 1H),
3.37- 3.28 (m, 2H)
(500 MHz, Methanol-d4) 6 10.66 (s, 1H), 8.58 (s, 1H), 8.02 (d,
1-11 390.1 2.65 1H), 7.94 (d, 1H), 7.77 (dd, 1H), 7.37 (d, 1H),
6.94 (d, 1H), 3.84 -
3.68 (m, 8H), 2.20 (s, 3H)
(500 MHz, DMSO-d6) 6 10.35 (dt, 1H), 8.47 (s, 1H), 7.89 (dt,
1-12 415.2 2.6 1H), 7.76 (s, 1H), 7.72 (dd, 1H), 7.58 (dd, 1H),
7.53 (s, 1H), 7.39
(d, 1H), 6.92 (d, 1H), 4.63 (dd, 1H), 4.30 - 4.22 (m, 1H), 4.13 -
4.00 (m, 2H), 3.78 (td, 1H), 3.10 (td, 1H), 3.05 (dd, 1H)
(500 MHz, Methanol-d4) 6 10.18 (tt, 1H), 8.45 (s, 1H), 8.30 (d,
1-13 439.1 2.18 1H), 7.78 (dd, 1H), 7.60 (dd, 1H), 7.03 (t, 1H),
6.65 (d, 1H), 4.41
(s, 1H), 4.27 (d, 1H), 4.12 (ddd, 1H), 3.78 - 3.66 (m, 2H), 3.30
(dd, 1H), 3.22 - 3.14 (m, 2H), 3.05 (s, 3H), 2.95 (dd, 1H)
(500 MHz, DMSO-d6) 6 10.17 (d, 1H), 8.65 (s, 1H), 8.40 (d,
1-14 373.1 2.12 1H), 7.96 (dd, 1H), 7.72 (dd, 1H), 7.31 (t, 1H),
6.87 (d, 1H), 3.88
- 3.81 (m, 2H), 3.81 - 3.74 (m, 2H), 3.65 - 3.60 (m, 4H), 2.08 (s,
3H)
(500 MHz, DMSO-d6) 6 10.18 (d, 1H), 8.64 (s, 1H), 8.40 (d,
1-15 398.1 2.16 1H), 7.94 (d, 1H), 7.75 - 7.64 (m, 3H), 7.24 (t,
1H), 6.93 (d, 1H),
4.60 (dd, 1H), 4.09 - 4.00 (m, 1H), 3.72 (td, 1H), 3.26 - 3.16 (m,
1H)
1-16 487.2 2.71 ----
(500 MHz, Methanol-d4) 6 10.38 (dd, 1H), 8.83 (s, 1H), 8.47 (d,
1-17 439.1 2.25 1H), 8.11 -7.99 (m, 2H), 7.27 (d, 1H), 7.15 (td,
1H), 4.60 (ddd,
1H), 4.50 (dt, 1H), 4.10 (ddd, 1H), 3.77 - 3.64 (m, 2H), 3.30 -
3.22 (m, 2H), 3.05 (dd, 1H), 2.99 (s, 3H)
(500 MHz, Methanol-d4) 6 10.38 (d, 1H), 8.86 (s, 1H), 8.50 (d,
1-18 398.1 2.2 1H), 8.13 -7.98 (m, 2H), 7.76 (s, 2H), 7.29 (d,
1H), 7.01 (t, 1H),
4.71 (dt, 2H), 4.59 - 4.51 (m, 1H), 4.14 (ddd, 1H), 3.86 (td, 1H),
3.43 - 3.32 (m, -2H)
1-19 423.1 2.3 (500 MHz, Methanol-d4) 6 10.13 (dd, 1H), 8.73 (s,
1H), 8.33 (d,
1H), 7.95 (dd, 1H), 7.92 (dd, 1H), 6.91 (d, 1H), 4.54 (s, 1H), 4.36
214
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LCM
Cmpd LCMS
S (rt, '11 NMR
mm)
(s, 1H), 4.19 - 4.08 (m, 1H), 3.79 -3.66 (m, 2H), 3.34 (d, 3H),
3.13 (dd, 1H), 2.99 (s, 3H)
(500 MHz, DMSO-d6) 6 10.02 (d, 1H), 8.60 (s, 1H), 8.41 (d,
1-20 382.1 2.24 1H), 7.87 (d, 1H), 7.70 (s, 2H), 7.63 (dd, 1H),
6.92 (d, 1H), 4.60
(dd, 1H), 4.05 (dd, 1H), 3.71 (td, 1H), 3.22 (td, 2H)
(500 MHz, DMSO-d6) 6 10.03 (dd, 1H), 8.56 (d, 1H), 8.38 (dd,
1-21 405.1 2.26 1H), 7.86 (d, 1H), 7.61 (dd, 1H), 6.80 (dd1H),
3.94 - 3.68 (m,
2H), 3.64 (d, 3H), 3.23 (dd, 2H), 2.44 - 2.32 (m, 1H), 2.02 (d,
1H), 1.85- 1.73 (m, 1H), 1.67- 1.45 (m, 2H)
(500 MHz, DMSO-d6) 6 9.92 (s, 1H), 8.74 (s, 1H), 8.66 (d, 1H),
1-22 383.1 2.23 7.87 (d, 1H), 7.69 (d, 2H), 7.63 (d, 1H), 4.80 -
4.65 (m, 1H), 4.65
-4.48 (m, 2H), 4.11 -3.96 (m, 1H), 3.68 (d, 1H)
(500 MHz, DMSO-d6) 6 12.81 (s, 1H), 10.14 (d, 1H), 8.45 (d,
1-23 400.1 2.36 1H), 8.38 (dd, 1H), 7.91 (d, 1H), 7.70 (s, 2H),
6.86 (d, 1H), 4.59
(dd, 1H), 4.56 - 4.15 (m, 2H), 4.12 -4.01 (m, 1H), 3.71 (td, 1H),
3.24- 3.09 (m, 2H)
(500 MHz, DMSO-d6) 6 10.20 (d, 1H), 8.51 (s, 1H), 8.40 (d,
1-24 446 2.35 1H), 7.92 (d, 1H), 7.70 (s, 2H), 6.90 (d, 1H), 4.59
(dd, 1H), 4.09 -
4.00 (m, 1H), 3.70 (dd, 1H), 3.28 -3.12 (m, 2H)
(500 MHz, DMSO-d6) 6 10.35 (d, 1H), 8.39 (s, 1H), 8.29 (d,
1-25 469.1 2.5 1H), 7.88 (d, 1H), 7.22 (d, 1H), 6.43 (s, 1H),
3.81 - 3.42 (m, 5H),
3.10- 3.02 (m, 2H), 2.93 (s, 3H), 2.17 (s, 1H), 1.84 (s, 1H)
(400 MHz, DMSO-d6) 6 10.04 - 9.98 (m, 1H), 8.47 (s, 1H), 8.37
1-26 343.1 2.0 (d, J = 6.2 Hz, 1H), 7.85 - 7.77 (m, 1H), 7.69 (t,
J = 5.6 Hz, 1H),
7.52 (dd, J¨ 9.5, 2.1 Hz, 1H), 6.80 (d, J= 6.3 Hz, 1H), 3.91 (s,
4H), 3.30 (s, 3H), 2.62 (d, J = 6.8 Hz, 2H).
(400 MHz, DMSO-d6) 6 12.68 (s, 1H), 10.13 (dd, J = 2.2, 0.9
Hz, 1H), 8.42 (s, 1H), 8.28 (d, J = 5.9 Hz, 1H), 7.79 (dd, J = 9.5,
1-27 366.1 2.42 0.9 Hz, 1H), 7.69 (s, 1H), 7.49 (dd, J = 9.6, 2.1
Hz, 2H), 6.43 (d,
J = 6.1 Hz, 1H), 3.85 (d, J = 30.4 Hz, 1H), 3.63 (d, J = 35.1 Hz,
1H), 3.49 (d, J = 8.0 Hz, 2H), 2.42 (d, J = 18.1 Hz, 1H), 2.05 (s,
1H), 0.99 - 0.90 (m, 1H).
1-28 381.1 2.0 ----
1-29 456.1 1.89 ----
(400 MHz, DMSO-d6) 6 10.04 (dd, J = 2.1, 0.8 Hz, 1H), 8.42 (s,
1H), 8.31 (d, J = 6.3 Hz, 1H), 7.79 (dd, J = 9.5, 0.8 Hz, 1H), 7.49
1-30 405.1 2.25 (dd, J¨ 9.5, 2.2 Hz, 1H), 6.71 (d, J= 6.3 Hz,
1H), 3.30 (s, 2H),
3.05 (d, J = 0.9 Hz, 3H), 3.02 (d, J = 1.0 Hz, 3H), 2.97 (d, J
3.4 Hz, 1H), 2.86 (s, 2H), 1.91 (dd, J¨ 9.1, 4.9 Hz, 1H), 1.77 (d,
J= 11.5 Hz, 1H), 1.50 (t, J¨ 9.4 Hz, 2H).
1-31 453.1 2.55 (500 MHz, Methanol-d4) 6 10.33 (s, 1H), 8.39 (s,
1H), 8.15 (d,
1H), 7.74 (d, 1H), 7.54 (dd, 1H), 6.56 (d, 1H), 4.40 ( br s, 2H),
215
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LCM
Cmpd LCMS
S (rt, '11 NMR
mm)
3.22 (masked, 1H), 3.04 (d, 6H), 2.98 (s, 1H), 2.60 (m, 1H), 2.43
(m, 1H), 1.93 (m, 1H), 1.67 (m, 1H), 1.27 (d, 1H), 1.18 (qd, 1H),
0.93 (d, 3H).
(500 MHz, Methanol-d4) 6 10.33 (s, 1H), 8.39 (s, 1H), 8.15 (d,
1H), 7.74 (d, 1H), 7.54 (dd, 1H), 6.56 (d, 1H), 4.40 (br s, 2H),
1-32 453.1 2.55 3.22 (masked, 1H), 3.04 (d, 6H), 2.98 (s, 1H),
2.60 (m, 1H), 2.43
(m, 1H), 1.93 (m, 1H), 1.67 (m, 1H), 1.27 (d, 1H), 1.18 (qd, 1H),
0.93 (d, 3H).
1-33 443.1 2.37 ----
(500 MHz, Methanol-d4) 6 10.60 - 10.22 (m, 1H), 8.53 (s, 1H),
8.41 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 9.5 Hz, 1H), 7.73 (s, 2H),
1-34 443.1 2.37 7.68 (d, J¨ 9.3 Hz, 1H), 7.22 (d, J= 5.2 Hz, 1H),
5.05 (s, 1H),
4.64 (s, 1H), 4.50 (s, 1H), 3.29 - 3.19 (m, 1H), 2.99 (s, 1H), 1.38
(d, J = 6.3 Hz, 3H), 1.32 - 0.97 (m, 3H).
(500 MHz, DMSO-d6) 6 12.59 (s, 1H), 10.05 (m, 1H), 8.45 (m,
1-35 409.1 2.29 1H), 8.36 (m, 1H), 7.95 (d, 1H), 7.80 (d, 1H),
7.61 (d, 1H), 6.79
(m, 1H), 5.03-4.60 (m, 1H), 4.23-3.83 (m, 2H), 2.92 (m, 1H),
2.76 (m, 1H), 2.51 (m, 1H), 1.19 (m, 3H), 0.99 (m, 3H).
(500 MHz, DMSO-d6) 6 12.59 (s, 1H), 10.05 (m, 1H), 8.45 (m,
1-36 409.3 2.48 1H), 8.36 (m, 1H), 7.95 (d, 1H), 7.80 (d, 1H),
7.61 (d, 1H), 6.79
(m, 1H), 5.03-4.60 (m, 1H), 4.23-3.83 (m, 2H), 2.92 (m, 1H),
2.76 (m, 1H), 2.51 (m, 1H), 1.19 (m, 3H), 0.99 (m, 3H).
(500 MHz, DMSO-d6) 6 10.41 (m, 1H), 8.54 (s, 1H), 8.35 (d,
1-37 443.4 2.45 1H), 7.96 (d, 1H), 7.66-7.61 (m, 3H), 6.85 (m,
1H), 5.92-5.45 (m,
1H), 4.06 (m, 1H), 2.89 (m, 1H), 2.80-2.65 (m, 1H), 2.55 (m,
1H), 1.18 (m, 3H), 0.98 (m, 3H).
1-38 443.4 2.45 ----
(500 MHz, Methanol-d4) 6 10.37 (s, 1H), 8.47 (s, 1H), 8.27 (d,
1-39 429.4 2.35 1H), 7.82 (d, 1H), 7.76 (s, 1H), 7.64 (d, 1H),
6.72 (d, 1H), 4.47
(s, 2H), 4.00 (d, 1H), 3.07-2.97 (m, 2H), 1.26 (d, 3H).
1-40 429.4 2.35 ----
(500 MHz, DMSO-d6) 6 10.11 (s, 1H), 8.67 (s, 1H), 8.48 (d, J
5.3 Hz, 1H), 7.92 (d, J = 9.6 Hz, 1H), 7.62 (dd, J = 9.3, 1.7 Hz,
1-41 487.3 2.79 1H), 7.33 (d, J = 5.3 Hz, 1H), 7.25 (t, J = 55.8
Hz, 1H), 7.25 (s,
1H), 5.12 (d, J= 15.6 Hz, 1H),4.73 (d, J= 15.0 Hz, 1H), 3.47 -
3.42 (m, 1H), 3.01 - 2.84 (m, 3H), 2.96 (s, 3H), 2.23 (s, 2H), 1.07
(d, J¨ 6.6 Hz, 3H).
(500 MHz, Methanol-d4) 6 10.39 - 10.32 (m, 1H), 8.72 (d, J =
1-42 427.8 2.2 7.0 Hz, 1H), 8.53 - 8.38 (m, 2H), 7.84 - 7.78 (m,
1H), 7.59 (d, J
18.5 Hz, 1H), 6.94 (dd, J = 18.3, 6.5 Hz, 1H), 5.33 (s, 1H), 5.14
(d, J = 4.4 Hz, 1H), 4.89 (d, J = 4.1 Hz, 1H), 4.45 (d, J = 14.7
216
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LCM
Cmpd LCMS
'11 NMR
No. (ES+)
mm)
Hz, 1H), 4.09 (dq, J = 6.7, 3.8 Hz, 1H), 3.80 (dd, J = 14.8, 3.4
Hz, 1H), 3.65 - 3.54 (m, 1H), 3.29 (d, J= 14.1 Hz, 1H), 1.56 (dd,
J= 6.7, 2.1 Hz, 3H), 1.31 (dd, J = 12.3, 7.0 Hz, 3H).
(500 MHz, Methanol-d4) 6 10.38 - 10.32 (m, 1H), 8.75 (s, 1H),
8.34 (d, J = 6.9 Hz, 1H), 8.04 (d, J = 9.4 Hz, 1H), 7.94 (dd, J =
1-43 404.1 2.24 9.4, 1.8 Hz, 1H), 6.99 (d, J = 6.9 Hz, 1H), 4.79 - 4.65
(m, 1H),
4.65 - 4.47 (m, 1H), 4.01 -3.88 (m, 2H), 3.65 (dd, J= 9.5, 8.4
Hz, 1H), 3.29 - 3.17 (m, 3H), 3.12 (ddd, J= 13.3, 12.0, 3.4 Hz,
1H).
(500 MHz, DMSO-d6) 6 10.35 (s, 1H), 8.73 (s, 1H), 8.47 (d, J
5.2 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.65
1-44 416.1 2.37 (s, 2H), 7.34 (d, J = 5.3 Hz, 1H), 4.63 - 4.54 (m, 2H),
4.46 (d, J =
13.3 Hz, 1H), 4.07 - 3.99 (m, 1H), 3.72 (td, J = 11.6, 2.9 Hz, 1H),
3.22 (d, J= 11.8 Hz, 1H).
(500 MHz, Methanol-d4) 6 10.29 (s, 1H), 8.77 (s, 1H), 8.33 (d, J
1-45 = 7.2 Hz, 1H), 8.06 (dt, J = 9.5, 0.8 Hz, 1H), 7.97 (dd,
J = 9.4,
416.2 2.33 1.8 Hz, 1H), 7.76 (s, 2H), 7.05 (d, J = 7.2 Hz, 1H),
4.76 (dd, J =
10.6, 2.7 Hz, 1H), 4.19 (ddd, J= 11.8,3.8, 1.6 Hz, 1H), 3.88 (td,
J= 11.8, 2.8 Hz, 1H), 3.59 - 3.41 (m, 2H).
1-46 433.3 2.53 ----
1-47 433.2 2.53 ----
(500 MHz, Methanol-d4) 6 10.01 (d, J = 7.0 Hz, 1H), 8.62 (s,
1H), 8.22 (d, J = 7.3 Hz, 1H), 7.82 (dd, J = 8.7, 0.6 Hz, 1H), 7.02
1-48 377.1 2.19 (d, J= 7.3 Hz, 1H), 4.58 (s, 1H), 4.30 (s, 1H), 3.76
(dd, J = 13.5,
9.4 Hz, 1H), 3.60 (t, J= 11.7 Hz, 1H), 2.71 (tt, J = 9.4, 4.1 Hz,
1H), 2.21 -2.12 (m, 1H), 2.08- 1.94 (m, 2H), 1.83 - 1.71 (m,
1H).
(500 MHz, Methanol-d4) 6 10.12 (d, J = 6.9 Hz, 1H), 8.63 (s,
1H), 8.29 (dd, J = 7.0, 0.6 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 6.96
1-49 423.0 2.29 (d, J= 7.1 Hz, 1H), 4.50 (s, 1H), 4.19 (s, 1H), 3.89
(tt, J= 8.5,
3.9 Hz, 1H), 3.61 -3.59 (m, 7H), 3.55 (dd, J = 13.2, 8.6 Hz, 1H),
2.25 - 2.16 (m, 1H), 2.05 (ddq, J= 13.4, 6.9, 3.9, 3.4 Hz, 1H),
1.90 - 1.76 (m, 2H).
(500 MHz, Methanol-d4) 6 10.05 (dd, J = 2.0, 0.9 Hz, 1H), 8.70
(s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.93 (dd, J = 9.5, 0.8 Hz, 1H),
1-50 385.1 2.32 7.85 (dd, J= 9.5, 2.0 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H),
5.37 (s,
1H), 4.06 (s, 1H), 3.59 (dd, J = 13.9, 3.2 Hz, 1H), 3.04 (dt, J =
12.7, 4.5 Hz, 1H), 2.40 - 2.29 (m, 2H), 1.68 - 1.61 (m, 1H), 1.39
(d, J= 6.9 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H).
(500 MHz, Methanol-d4) 6 10.04 (s, 1H), 8.71 (s, 1H), 8.29 (d, J
1-51 385.1 2.38 = 7.1 Hz, 1H), 7.94 (dd, J= 9.7, 0.9 Hz, 1H), 7.87
(dd, J= 9.5,
2.0 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 2.96 (s, 1H), 2.80 (d, J =
217
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LCM
Cmpd LCMS
S (rt, '11 NMR
mm)
11.6 Hz, 1H), 1.89(s, 1H), 1.77 (t, J= 11.9 Hz, 2H), 1.35 (d, J=
6.9 Hz, 3H), 1.17 (s, 3H).
(500 MHz, Methanol-d4) 6 10.06 (d, J = 7.0 Hz, 1H), 8.65 (s,
1H), 8.25 (d, J = 7.3 Hz, 1H), 7.84 (dd, J = 8.7, 0.6 Hz, 1H), 7.02
1-52 403.1 2.41 (d, J¨ 7.3 Hz, 1H), 5.39 (s, 1H), 4.07 (s, 1H),
3.62 (dd, J= 13.7,
3.3 Hz, 1H), 3.04 (dt, J = 12.8, 4.7 Hz, 1H), 2.43 - 2.27 (m, 2H),
1.71 - 1.61 (m, 1H), 1.40 (d, J¨ 7.0 Hz, 3H), 1.14 (d, J 6.8 Hz,
3H).
1H NMR (500 MHz, Methanol-d4) 6 10.06 (d, J = 7.0 Hz, 1H),
8.66 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 7.84 (dd, J = 8.8, 0.6 Hz,
1-53 403.1 2.47 1H), 7.05 (d, J = 7.3 Hz, 1H), 5.66 (s, 1H), 4.06
(s, 1H), 2.99 (s,
2H), 2.87 - 2.77 (m, 1H), 1.89(s, 1H), 1.77 (q, J¨ 12.0 Hz, 2H),
1.36 (s, 3H), 1.17 (s, 3H).
(400 MHz, DMSO-d6) 6 10.02 (s, 1H), 8.61 ¨ 8.37 (m, 2H), 7.81
1-54 412 1.92 (d, 1H), 7.52 (d, 1H), 6.89 (d, 1H), 5.08 (dd, 1H),
3.92 (t, 2H),
2.86 (t, 1H), 2.41 (s, 3H), 1.44 (s, 1H), 1.28 (d, 3H).
(400 MHz, DMSO-d6) 6 11.76 (s, 1H), 10.0 (s, 1H), 8.43 (m,
1-55 380 0.89 2H), 7.76 (d, 1H), 7.51 (m, 2H), 6.88 (m, 2H), 3.07 (m,
2H), 2.76
(s, 1H), 2.03 (m, 1H), 1.55 (m, 3H).
(400 MHz, DMSO-d6) 6 8.48 (s, 1H), 8.41 (d, 1H), 7.92 (d, 1H),
1-56 430 2.22 6.89 (d, 1H), 5.07 (dd, 1H), 4.01 ¨ 3.70 (m, 1H), 2.84
(dd, 1H),
2.41 (s, 3H), 2.08 (s, 1H), 1.28 (d, 3H).
(400 MHz, DMSO-d6) 6 11.90(s, 1H), 10.12(d, 1H), 8.50 ¨ 8.16
1_57 398 0.98 (m, 2H), 7.89 (d, 1H), 7.58 (s, 1H), 6.96 ¨ 6.59 (m,
2H), 3.11 (dd,
2H), 2.77 (dq, 1H), 2.15 ¨2.01 (m, 1H), 1.89 ¨ 1.67 (m, 2H),
1.60 (dd, 1H).
(400 MHz, DMSO-d6) 6 12.53 (s, 1H), 10.02 (s, 1H), 8.52 ¨ 8.11
1-58 441 1.27 (m, 2H), 7.90 (d, 1H), 7.68 (s, 2H), 6.83 (d, 1H), 3.22
(dd, 1H),
3.07 (t, 1H), 2.63 ¨2.52 (m, 1H), 1.99 (d, 1H), 1.92 ¨ 1.65 (m,
2H), 1.50(d, 1H).
(400 MHz, DMSO-d6) 6 10.14 (d, 1H), 10.01 (s, 1H), 8.41 (s,
1-59 455 1.40 1H), 8.32 (d, 1H), 7.97 ¨ 7.72 (m, 2H), 7.39 (s, 1H),
6.83 (d, 1H),
3.78 (s, 3H), 3.22 (dd, 1H), 3.08 (t, 1H), 1.98 (d, 1H), 1.82 (s,
2H), 1.51 (t, 1H).
1H NMR (400 MHz, DMSO-d6) 6 10.40 (s, 1H), 8.53 (s, 1H),
8.30 (d, J = 6.2 Hz, 1H), 7.95 (d, J = 9.4 Hz, 1H), 7.67 (d, J =
1-60 442 1.84 9.4 Hz, 1H), 7.49 (d, J= 39.5 Hz, 1H), 7.39 ¨ 7.19 (m,
2H), 6.82
(d, J¨ 6.1 Hz, 1H), 3.74 (s, 4H), 3.47 (s, 1H), 3.05 (s, 1H), 2.05
¨ 1.87 (m, 2H), 1.72 (d, J = 10.6 Hz, 1H), 0.99 (d, J = 6.7 Hz,
3H).
1H NMR (400 MHz, DMSO-d6) 6 10.37 (s, 1H), 8.52 (s, 1H),
1-61 442 1.91 8.32 (d, J = 6.2 Hz, 1H), 7.94 (d, J = 9.4 Hz, 1H),
7.82¨ 7.54
(m, 2H), 7.40 (s, 1H), 6.87 (d, J = 6.3 Hz, 1H), 3.80 (s, 3H), 2.79
218
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LCM
Cmpd LCMS
S (rt, '11 NMR
mm)
(t , J = 12.1 Hz, 1H), 2.68 (t, J = 13.1 Hz, 1H), 2.58 (t, J = 12.3
Hz, 1H), 2.05 (d, J= 12.8 Hz, 1H), 1.71 (s, 1H), 1.31 (q, J = 11.9
Hz, 1H), 1.00 (d, J = 6.4 Hz, 3H).
1-62 412
1-63 412
1H NMR (400 MHz, DMSO-d6) 6 10.10 (s, 1H), 8.43 (s, 1H),
1-64 398 1.65 8.34 (s, 1H), 7.80 (d, J = 9.9 Hz, 1H), 7.51 (d, J =
9.5 Hz, 1H),
6.64 (s, 1H), 6.50 (s, 1H), 4.27 ¨ 3.56 (m, 5H), 2.56 (s, 1H), 2.39
(s, 3H).
1H NMR (400 MHz, DMSO-d6) 6 10.00 (s, 1H), 8.42 (d, J = 5.9
Hz, 1H), 8.33 (d, J = 6.2 Hz, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.49
1-65 381 1.59 (d, J= 10.1 Hz, 2H), 6.78 (dd, J = 16.5, 6.3 Hz, 1H),
4.43 (s,
2H), 3.00 (q, J = 16.5, 14.9 Hz, 1H), 2.94 ¨ 2.76 (m, 1H), 1.82
(d, J = 12.5 Hz, 2H), 1.68 ¨ 1.42 (m, 2H).
1H NMR (400 MHz, DMSO-d6) 6 9.98 (dd, J = 2.2, 0.9 Hz, 1H),
8.86 (d, J= 1.6 Hz, 1H), 8.41 (s, 1H), 8.33 (d, J = 6.3 Hz, 1H),
7.78 (dd, J = 9.5, 0.8 Hz, 1H), 7.48 (dd, J = 9.5, 2.2 Hz, 1H),
1-66 381 1.65 6.83 (d, J= 6.3 Hz, 1H), 6.68 (d, J = 1.7 Hz, 1H),
4.58 (s, 1H),
4.34 (s, 1H), 3.22 (ddd, J = 13.6, 11.4, 2.8 Hz, 1H), 3.03 (tt, J-
10.4, 3.9 Hz, 1H), 2.12 (d, J= 10.0 Hz, 1H), 1.84 (dtd, J = 13.9,
10.3, 9.3, 4.2 Hz, 2H), 1.63 (q, J= 12.9 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) 6 10.13 ¨ 9.94 (m, 1H), 8.41 (d,
J = 3.0 Hz, 1H), 8.31 (d, J = 6.2 Hz, 1H), 7.79 (d, J = 9.9 Hz,
1-67 342 1.22 1H), 7.50 (d, J = 9.2 Hz, 1H), 6.63 (d, J = 6.3 Hz,
1H), 5.70 (d, J
= 2.5 Hz, 1H), 4.37 (s, 1H), 3.68 (d, J = 13.1 Hz, 2H), 2.13 (s,
1H), 1.68 (d, J = 10.3 Hz, 1H), 1.21 (s, 1H), 0.75 (d, J= 9.4 Hz,
1H), 0.36 (d, J = 5.0 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) 6 10.04 (d, J = 8.7 Hz, 1H),
8.52 (s, 1H), 8.35 (d, J = 6.3 Hz, 1H), 8.06 (s, 1H), 7.80 (d, J
9.4 Hz, 1H), 7.55 ¨ 7.43 (m, 1H), 6.77 (d, J = 6.4 Hz, 1H), 4.45
1-68 413 1.38 (s, 2H), 4.25 (d, J = 8.7 Hz, 1H), 3.98 (t, J = 9.9
Hz, 1H), 2.92 (t,
J= 12.3 Hz, 1H), 2.74 (t, J= 12.5 Hz, 1H), 1.79 (dd, J= 21.9,
11.6 Hz, 2H), 1.58 (d, J = 11.5 Hz, 1H), 1.39 (dt, J = 23.5, 14.1
Hz, 2H), 1.29 (d, J = 11.8 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) 6 10.41 (s, 1H), 8.55 (d, J = 2.9
1-69 390 1.57 Hz, 1H), 8.38 (d, J= 5.9 Hz, 1H), 7.95 (d, J= 9.5 Hz,
1H), 7.68
(d, J = 9.5 Hz, 1H), 6.72 (s, 1H), 4.41 (s, 2H), 3.94 (dd, J = 47.0,
23.2 Hz, 2H), 3.57 (s, 2H), 2.81 (s, 3H), 1.85 (s, 2H).
1H NMIR (400 MHz, DMSO-d6) 6 10.50(s, 1H), 8.52 (d, J= 1.5
1-70 484 2.65 Hz, 1H), 8.34 (dd, J= 6.1, 1.5 Hz, 1H), 7.94 (d, J = 9.4
Hz, 1H),
7.67 (d, J = 9.5 Hz, 1H), 6.52 (d, J = 6.1 Hz, 1H), 4.25 (s, 1H),
3.89 (s, 2H), 3.19 (s, 1H), 3.12 ¨2.94 (m, 1H), 2.30 (dt, J = 14.3,
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S (rt, '11 NMR
mm)
7.7 Hz, 1H), 2.12 (dq, J = 16.2, 8.8, 7.9 Hz, 2H), 1.92 (ddp, J
34.3, 13.4, 7.0, 6.5 Hz, 2H), 1.72 (dt, J= 13.0, 6.4 Hz, 1H), 1.26
(s, 6H).
1H NMR (400 MHz, DMSO-d6) 6 10.40(s, 1H), 8.51 (d, J= 1.3
Hz, 1H), 8.30 (dd, J = 6.4, 1.4 Hz, 1H), 7.94 (d, J = 9.4 Hz, 1H),
1-71 362 2.43 7.67 (d, J = 9.3 Hz, 1H), 6.78 (d, J = 6.3 Hz, 1H),
4.33 (s, 1H),
3.02 (t, J = 12.0 Hz, 1H), 1.79 (dd, J = 33.2, 13.3 Hz, 2H), 1.70 ¨
1.41 (m, 2H), 1.41 ¨ 1.17 (m, 1H), 0.95 (d, J = 6.5 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) 6 10.14 (d, J = 19.7 Hz, 1H),
8.43 (d, J= 8.7 Hz, 1H), 8.31 (dd, J = 16.7, 6.1 Hz, 1H), 8.17 (d,
1-72 425 1.6 J= 1.5 Hz, 1H), 7.79 (s, 1H), 7.50(s, 1H), 6.46 (dd,
J= 19.6, 6.0
Hz, 1H), 5.80 (d, J= 20.5 Hz, 1H), 4.84 (p, J= 6.9 Hz, 1H), 3.89
(dt, J = 45.7, 12.7 Hz, 3H), 3.66 (d, J = 10.1 Hz, 2H), 2.31 (s,
1H), 1.51 (d, J = 6.7 Hz, 7H).
1H NMR (400 MHz, DMSO-d6) 6 10.14 (d, J = 7.5 Hz, 1H),
8.47 (s, 1H), 8.40 (d, J = 6.2 Hz, 1H), 7.90 (d, J = 9.8 Hz, 1H),
1_73 459 2.8 7.48 (s, 1H), 7.44¨ 7.25 (m, 3H), 6.84 (d, J = 6.3
Hz, 1H), 5.14
(d, J = 7.1 Hz, 1H), 4.85 (d, J = 2.2 Hz, 1H), 4.21 ¨ 3.97 (m,
1H), 3.78 (dd, J = 11.2, 4.1 Hz, 1H), 3.55 (td, J = 11.5, 3.7 Hz,
1H), 3.42 (td, J= 12.6, 4.3 Hz, 1H), 1.41 (d, J= 6.6 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) 6 10.42 (s, 1H), 8.51 (s, 1H),
8.31 (d, J = 6.1 Hz, 1H), 7.94 (d, J = 9.4 Hz, 1H), 7.67 (d, J =
1-74 376 1.44 9.5 Hz, 1H), 6.66 (d, J= 6.2 Hz, 1H), 5.69 (d, J= 2.6 Hz,
1H),
4.34 (s, 1H), 3.68 (d, J = 13.1 Hz, 2H), 2.22 ¨2.04 (m, 1H), 1.76
¨1.50 (m, 1H), 1.22 (s, 1H), 0.76 (dd, J = 10.3, 5.1 Hz, 1H), 0.36
(t, J = 5.1 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) 6 10.03 (d, J = 4.9 Hz, 1H),
8.40 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 9.4 Hz, 1H), 7.61 ¨ 7.31
(m, 1H), 6.48 (d, J = 6.0 Hz, 1H), 4.18 (d, J = 35.3 Hz, 1H),3.86
1-75 450 2.29 (s, 2H), 3.17 (d, J = 8.8 Hz, 1H), 3.04 (p, J = 7.1 Hz,
1H), 2.30
(dt, J = 14.7, 7.7 Hz, 1H), 2.12 (dp, J = 16.1, 8.0, 7.5 Hz, 2H),
2.04¨ 1.76 (m, 2H), 1.72 (dt, J = 13.1, 6.6 Hz, 1H), 1.36¨ 1.13
(m, 6H).
1H NMR (400 MHz, DMSO-d6) 6 10.0 (s, 1H), 8.4 (s, 1H), 8.25
1-76 439 1.3 (d, 1H), 8.16 (s, 1H), 7.76 (d, 1H), 7.51 (d, 1H),
6.77 (d, 1H),
5.25 (s, 1H), 4.75 (m, 1H), 3.70 (m, 1H), 2.22 (m, 1H), 1,92 (m,
2H), 1.61 (m, 1H), 1.46 (m, 6H).
1H NMR (400 MHz, DMSO-d6) 6 10.14 (d, J = 7.6 Hz, 1H),
10.01 (s, 1H), 8.41 (s, 1H), 8.32 (d, J = 6.3 Hz, 1H), 7.97 ¨ 7.72
1-77 455 1.4 (m, 2H), 7.39 (s, 1H), 6.83 (d, J= 6.3 Hz, 1H), 3.78
(s, 3H), 3.22
(dd, J= 13.2, 10.9 Hz, 1H), 3.08 (t, J = 12.4 Hz, 1H), 1.98 (d, J
= 11.8 Hz, 1H), 1.82(s, 2H), 1.51 (t, J = 12.9 Hz, 1H).
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Cmpd LCMS
S (rt, '11 NMR
mm)
1H NMR (400 MHz, DMSO-d6) 6 10.03 (d, J = 13.8 Hz, 1H),
8.45 (s, 1H), 8.29 (t, J = 6.5 Hz, 1H), 7.78 (dd, J = 9.8, 5.5 Hz,
1-78 384 1.39 1H), 7.49 (d, J = 9.6 Hz, 1H), 6.84¨ 6.47 (m, 1H),
1.93 ¨ 1.46
(m, 5H), 1.22¨ 0.98 (m, 1H), 0.91 (dt, J = 13.2, 4.6 Hz, 1H).
Several peaks overlap with solvent peak.
1H NMR (400 MHz, DMSO-d6) 6 10.02 (s, 1H), 8.51 ¨8.16 (m,
1-79 376 2.0 2H), 7.78 (d, J = 9.5 Hz, 1H), 7.64 ¨ 7.36 (m, 1H),
6.67 (d, J
6.3 Hz, 1H), 4.40 ¨ 4.06 (m, 1H), 3.80 ¨ 3.54 (m, 2H), 2.01 ¨
1.64 (m, 3H), 1.26 (s, 3H).
1H NMR (400 MHz, DMSO-d6) 6 10.42 (s, 1H), 8.55 (s, 1H),
1-80 377 1.46 8.40 (d, J = 6.1 Hz, 1H), 7.95 (d, J = 9.4 Hz, 1H), 7.68
(d, J
9.5 Hz, 2H), 6.72 (s, 1H), 4.31 (s, 2H), 4.19 ¨ 3.63 (m, 2H), 1.77
(d, J = 6.6 Hz, 2H).
1H NMR (400 MHz, DMSO-d6) 6 10.15 (d, J= 7.6 Hz, 1H),
8.46¨ 8.16 (m, 2H), 7.90 (d, J = 9.9 Hz, 1H), 7.63 (d, J = 7.7
1-81 424 1.79 Hz, 2H), 7.33 (dt, J = 40.4, 7.4 Hz, 2H), 6.76 (d, J =
6.3 Hz, 1H),
5.06 (s, 1H), 3.44 (d, J = 13.4 Hz, 1H), 3.15 (t, J = 12.2 Hz, 1H),
2.16 (td, J= 12.6, 4.1 Hz, 1H), 1.84 (d, J= 13.1 Hz, 1H), 1.65
(d, J= 12.9 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) 6 10.01 (s, 1H), 8.38 (s, 1H),
8.26 (d, J = 6.3 Hz, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.49 (d, J
9.2 Hz, 1H), 6.69 (d, J = 6.4 Hz, 1H), 4.73 (s, 1H), 2.96 (d, J =
1-82 442 1.9 12.9 Hz, 1H), 2.84 (t, J = 13.5 Hz, 1H), 2.61 (d, J =
9.3 Hz, 1H),
2.43 (t, J= 9.9 Hz, 1H), 2.36 ¨ 2.15 (m, 2H), 1.87 (d, J= 12.6
Hz, 1H), 1.72 (dt, J= 24.0, 11.6 Hz, 3H), 1.55 (q, J= 13.0, 12.2
Hz, 2H).
1H NMR (400 MHz, DMSO-d6) 6 10.06 (s, 1H), 8.44 ¨ 8.21 (m,
1-83 438 1.7 2H), 7.87 (d, J = 9.9 Hz, 1H), 7.44¨ 7.13 (m, 5H),
6.79 (d, J
6.1 Hz, 1H), 4.46 (s, 1H), 4.17 (s, 1H), 3.90 (s, 1H), 3.65 (s, 1H),
2.14 (s, 1H), 1.75 (s, 2H).
1H NMR (400 MHz, DMSO-d6) 6
10.16 (m, 1H), 8.47 (s, 1H), 8.25 (d, 1H), 7.79 (d, 1H), 7.50 (d,
1-84 388 2.2 1H), 7.31 (m, 4H), 7.24 (m, 1H), 6.5 (m, 1H), 4.07
(m, 1H), 2.22
(m, 1H), 1.25 (m, 1H), 1.0 (m, 1H). Several peaks overlap with
solvent peak.
1H NMR (400 MHz, DMSO-d6) 6 10.20 (d, J = 7.5 Hz, 1H),
8.45 (s, 1H), 8.28 (d, J = 6.2 Hz, 1H), 7.91 (d, J = 9.8 Hz, 1H),
1-85 438 1.95 7.49 (d, J = 7.8 Hz, 2H), 7.27 (t, J = 7.6 Hz, 2H), 7.15
(t, J = 7.3
Hz, 1H), 6.80 (s, 1H), 4.69 (s, 1H), 3.78 (d, J = 13.5 Hz, 2H),
3.51 (s, 3H), 2.07 (s, 2H), 1.70 (s, 1H).
1H NMR (400 MHz, DMSO-d6) 6 10.40 (s, 1H), 10.12 (d, J =
1-86 452 1.0 7.5 Hz, 1H), 8.48 ¨ 8.22 (m, 4H), 7.89 (d, J = 9.9
Hz, 1H), 7.65 ¨
7.44 (m, 2H), 6.85 (d, J = 6.3 Hz, 1H), 3.12 (t, J = 12.5 Hz, 1H),
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S (rt, 1H NMR
No. (ES+)
mm)
2.66 (d, J = 5.6 Hz, 1H), 2.06 (d, J = 12.3 Hz, 1H), 1.84 (t, J
12.4 Hz, 2H), 1.53 (t, J¨ 12.4 Hz, 1H).
(500 MHz, Methanol-d4) 6 10.17¨ 10.04 (m, 1H), 8.44 (s, 1H),
8.28 (d, 1H), 7.70 (d, 1H), 7.49 (d, 1H), 6.69 (d, 1H), 4.43 (s,
1-87 329.1 0.80 1H), 4.31 (s, 1H), 3.18 (t, 1H), 3.04 ¨ 2.92 (m, 1H),
2.92 ¨ 2.81
(m, 1H), 2.16 ¨ 2.02 (m, 1H), 1.95 ¨ 1.84 (m, 1H), 1.64(q, 1H),
1.59¨ 1.40(m, 1H).
(400 MHz, DMSO-d6) 6 10.11 (d, 1H), 8.66 ¨ 8.55 (m, 1H), 8.46
1-88 411.1 1.49 ¨8.33 (m, 2H), 7.95 ¨ 7.80 (m, 2H), 7.56(d, 1H), 7.38
(dd, 1H),
6.83 (d, 1H), 4.74 (s, 1H), 4.66 (dd, 1H), 4.35 (s, 1H), 4.26 ¨ 4.13
(m, 1H), 3.81 (td, 1H), 3.28 ¨3.16 (m, 1H), 3.16¨ 3.06 (m, 1H).
1H NMR (400 MHz, DMSO-d6) 6 10.37 (s,1H), 8.60 (s, 1H), 8.44
(d, J = 6.2 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.68 (dd, J = 9.4,
1-89 446.2 1.46 2.0 Hz, 1H), 6.92 (d, J= 6.3 Hz, 1H), 5.09 (dd, J= 11.0,
2.8 Hz,
1H), 4.80 (s, 1H), 4.49 (s, 1H), 3.92 (s, 1H), 2.92 ¨ 2.81 (m, 1H),
2.41 (s, 3H), 1.28 (d, J = 6.2 Hz, 3H).
111 NMR (400 MHz, DMSO-d6) 6 10.37 (s, 1H), 8.60 (s, 1H),
8.44 (d, J = 6.2 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.68 (dd, J =
1-90 446.2 1.46 9.4, 2.0 Hz, 1H), 6.92 (d, J¨ 6.3 Hz, 1H), 5.09 (dd, J=
11.0, 2.8
Hz, 1H), 4.80 (s, 1H), 4.49 (s, 1H), 3.92 (s, 1H), 2.92 ¨2.81 (m,
1H), 2.41 (s, 3H), 1.28 (d, J = 6.2 Hz, 3H).
111 NMR (400 MHz, DMSO-d6) 6 10.40 (d, J = 1.4 Hz, 1H), 8.61
(s, 1H), 8.44 (d, J = 6.2 Hz, 1H), 7.92 (dd, J = 9.3, 1.0 Hz, 1H),
1-91 403.2 1.24 7.70 (dd, J = 9.3, 1.8 Hz, 1H), 6.92 (d, J = 6.3 Hz,
1H), 5.07 (dd,
J = 11.0, 2.8 Hz, 1H), 4.50 (s, 1H), 3.92 (ddd, J = 10.9, 6.3, 2.7
Hz, 1H), 2.91 ¨2.80 (m, 1H), 2.41 (s, 3H), 1.28 (d, J = 6.2 Hz,
3H).
1H NMR (400 MHz, DMSO-d6) 6 10.40 (d, J = 1.4 Hz, 1H), 8.61
(s, 1H), 8.44 (d, J = 6.2 Hz, 1H), 7.92 (dd, J = 9.3, 1.0 Hz, 1H),
1-92 403.2 1.26 7.70 (dd, J = 9.3, 1.8 Hz, 1H), 6.92 (d, J = 6.3 Hz,
1H), 5.07 (dd,
J = 11.0, 2.8 Hz, 1H), 4.50 (s, 1H), 3.92 (ddd, J = 10.9, 6.3, 2.7
Hz, 1H), 2.91 ¨2.80 (m, 1H), 2.41 (s, 3H), 1.28 (d, J = 6.2 Hz,
3H).
1H NMR (400 MHz, DMSO-d6) 6 10.36 (s, 1H), 8.58 (s, 1H),
8.42 (d, J = 6.1 Hz, 1H), 7.95 (d, J = 9.4 Hz, 1H), 7.67 (dd, J =
1-93 446.3 1.28 9.4, 1.9 Hz, 1H), 6.89 (d, J¨ 6.3 Hz, 1H), 5.01 (dd,
J= 11.1,2.7
Hz, 1H), 4.61 (d, J = 103.5 Hz, 2H), 4.07 ¨ 3.83 (m, 1H), 2.85
(dd, J¨ 13.2, 10.8 Hz, 1H), 1.26 (d, J 6.2 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) 6 10.42(s, 1H), 8.61 (s, 1H),
8.44 (d, J = 6.3 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.70 (dd, J =
1-94 403.2 1.07 9.3, 1.8 Hz, 1H), 6.92 (d, J¨ 6.3 Hz, 1H), 4.99 (dd,
J 11.1,2.7
Hz, 1H), 4.66 (d, J = 106.3 Hz, 2H), 3.98 ¨ 3.83 (m, 1H), 2.94 ¨
2.76 (m, 1H), 1.27 (d, J = 6.2 Hz, 3H).
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S (rt, 1H NMR
No. (ES+)
mm)
111 NMR (400 MHz, DMSO-d6) 6 10.00 (s, 1H), 8.49 (d, J = 2.3
Hz, 1H), 8.44 - 8.37 (m, 1H), 7.79 (dd, J = 9.6, 2.2 Hz, 1H), 7.49
1-95 412.2 1.11 (dd, J- 9.5, 2.5 Hz, 1H), 6.90 - 6.83 (m, 1H), 4.99
(dd, J 11.1,
2.7 Hz, 1H), 4.78 (s, 1H), 4.48 (s, 1H), 3.90 (t, J= 8.4 Hz, 1H),
2.84 (t, J = 12.0 Hz, 1H), 2.53 (d, J = 23.2 Hz, 3H), 1.26 (d, J
5.9 Hz, 3H).
111 NMR (400 MHz, DMSO-d6) 6 9.98 (d, J = 2.6 Hz, 1H), 8.49
(d, J = 2.2 Hz, 1H), 8.36 (dd, J = 6.4, 2.2 Hz, 1H), 7.78 (dd, J =
1-96 384.1 1.29 9.5, 2.2 Hz, 1H), 7.57 -7.43 (m, 1H), 6.79 (dd, J =
6.5, 2.1 Hz,
1H), 4.48 (d, J = 40.8 Hz, 2H), 4.33 - 4.07 (m, 4H), 3.60 (d, J
7.8 Hz, 1H), 3.10 (t, J = 12.3 Hz, 1H), 2.92 (dt, J = 37.3, 12.3
Hz, 2H), 2.20 (d, J- 14.0 Hz, 1H), 1.82 (q, J- 11.5 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) 6 10.04 (s, 1H), 8.51 (d, J = 2.9
Hz, 1H), 8.43 -8.31 (m, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.52 (d, J
1-97 370.1 0.82 - 9.6 Hz, 1H), 6.83 (d, J= 6.3 Hz, 1H), 6.59 (s, 1H),
4.55 (d, J=
55.4 Hz, 2H), 3.71 (d, J = 11.1 Hz, 2H), 3.47 (t, J = 9.0 Hz, 1H),
3.15 -2.79 (m, 4H).
1H NMR (400 MHz, DMSO-d6) 6 10.00 (s, 1H), 8.51 (d, J = 2.1
Hz, 1H), 8.35 (dd, J = 6.3, 2.2 Hz, 1H), 7.80 (dd, J = 9.7, 2.3 Hz,
1-98 385.1 1.35 1H), 7.52 (d, J = 9.3 Hz, 1H), 7.34- 6.97 (m, 2H),
6.80 (d, J
6.4 Hz, 1H), 6.44 (s, 1H), 4.46 (d, J = 44.9 Hz, 2H), 4.26 - 4.12
(m, 1H), 3.22 - 2.90 (m, 4H), 2.77 (dt, J = 23.4, 12.1 Hz, 2H),
2.05 (d, J- 12.3 Hz, 1H), 1.69 (d, J= 11.9 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) 6 10.04 (s, 1H), 8.54 (d, J = 1.7
Hz, 1H), 8.48 - 8.37 (m, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.53 (d, J
1-99 371.1 0.91 - 9.8 Hz, 1H), 6.85 (d, J = 6.3 Hz, 1H), 4.79 (s,
1H), 4.56 (s,
1H), 4.48 (t, J = 8.6 Hz, 1H), 4.12 - 4.05 (m, 1H), 3.96 (dd, J
11.5, 8.3 Hz, 1H), 3.71 (d, J = 11.3 Hz, 1H), 3.05 (dt, J = 40.0,
12.6 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) 6 12.65(s, 1H), 10.03 (d, J- 2.1
Hz, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.33 (dd, J = 6.3, 1.9 Hz, 1H),
1-100 380.2 0.97 7.80 (dd, J = 9.7, 1.8 Hz, 1H), 7.74- 7.39 (m, 3H),
6.84 (dd, J
6.4, 1.9 Hz, 1H), 4.53 (s, 2H), 3.18 -2.98 (m, 2H), 2.76 (t, J
10.9 Hz, 1H), 2.10 (d, J 12.4 Hz, 1H), 1.84 (d, J- 13.0 Hz,
1H), 1.77- 1.50 (m, 2H).
1H NMR (400 MHz, DMSO-d6) 6 10.36(s, 1H), 8.51 (d, J- 1.8
Hz, 1H), 8.31 (dd, J- 6.4, 1.8 Hz, 1H), 7.93 (d, J= 9.4 Hz, 1H),
1-101 414.2 1.05 7.65 (d, J- 9.4 Hz, 1H), 7.56(s, 2H), 6.84 (d, J=
6.3 Hz, 1H),
4.45 (s, 2H), 3.09 (q, J = 11.9 Hz, 3H), 2.85 -2.60 (m, 1H), 2.12
- 1.96 (m, 1H), 1.81 (d, J = 12.7 Hz, 1H), 1.65 (tq, J = 24.5,
12.3, 11.5 Hz, 2H), 1.20 (t, J = 7.4 Hz, 1H).
1-102 357.1 1.1 1H NMR (400 MHz, DMSO-d6) 6 10.02 (s, 1H), 8.43 (d, J
= 2.2
Hz, 1H), 8.33 (d, J = 6.2 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.50
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S (rt, 1H NMR
No. (ES+)
mm)
(d, J = 9.6 Hz, 1H), 7.41 (s, 1H), 6.91 (s, 1H), 6.80 (d, J = 6.4
Hz, 1H), 4.42 (s, 2H), 3.09 (dt, J = 32.0, 12.4 Hz, 2H), 2.37 (s,
1H), 1.93 (d, J = 13.4 Hz, 1H), 1.74 (dt, J = 24.2, 13.3 Hz, 2H),
1.48 (t, J= 13.1 Hz, 1H).
1H NMR (300 MHz, DMSO-d6) 6 12.39 (s, 1H), 10.41 (s, 1H),
8.53 (s, 1H), 8.36 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.71 (s, 1H),
1-114 441 1.1 7.47 (s, 1H), 6.87 (s, 1H), 2.73 (d, J= 50.4Hz, 4H),
2.16 (d, J=
31.7Hz, 3H), 1.98 (s, 1H), 1.75 (s, 1H), 1.43 (s, 1H), 1.26 (s, 1H),
1.02 (d, J= 6.3Hz, 3H).
1H NMR (300 MHz, DMSO-d6) 6 12.49 (d, J = 28.6 Hz, 1H),
10.36 (s, 1H), 8.73 (s, 1H), 8.44 (d, J = 5.3 Hz, 1H), 7.96 (d, J =
1-115 443 1.2 9.4 Hz, 1H), 7.70 (d, J= 9.4 Hz, 1H), 7.60 ¨ 7.16 (m,
2H), 4.55
(d, J¨ 10.1 Hz, 3H), 3.80 (s, 1H), 3.09 (t, 1H), 2.78 (t, 1H), 2.37
¨ 2.05 (m, 3H), 1.23 (d, J = 6.1 Hz, 3H).1.2 min, 443).
1H NMR (300 MHz, DMSO-d6) 6 12.49 (d, J = 28.6 Hz, 1H),
10.36 (s, 1H), 8.73 (s, 1H), 8.44 (d, J = 5.3 Hz, 1H), 7.96 (d, J =
1-116 443 1.2 9.4 Hz, 1H), 7.70 (d, J= 9.4 Hz, 1H), 7.60 ¨ 7.16 (m,
2H), 4.55
(d, J¨ 10.1 Hz, 3H), 3.80 (s, 1H), 3.09 (t, 1H), 2.78 (t, 1H), 2.37
¨ 2.05 (m, 3H), 1.23 (d, J = 6.1 Hz, 3H).1.2 min, 443).
1H NMR (300 MHz, DMSO-d6) 6 12.84 (s, 1H), 10.37 (s, 1H),
8.73 (s, 1H), 8.45 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H),
1-117 429 1.4 7.79 (s, 1H), 7.74 - 7.65 (m, 1H), 7.55 (s, 1H), 7.33
(d, J¨ 5.3
Hz, 1H), 4.57 (dd, J = 25.6, 12.1 Hz, 3H), 3.79 (d, J = 7.2 Hz,
1H), 3.06 (t, J = 12.3 Hz, 1H), 2.79 (t, J = 11.8 Hz, 1H), 1.24 (d,
J= 6.2 Hz, 3H).
1H NMR (300 MHz, DMSO-d6) 6 12.84 (s, 1H), 10.37 (s, 1H),
8.73 (s, 1H), 8.45 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H),
1-118 429 1.4 7.79 (s, 1H), 7.74 - 7.65 (m, 1H), 7.55 (s, 1H), 7.33
(d, J¨ 5.3
Hz, 1H), 4.57 (dd, J = 25.6, 12.1 Hz, 3H), 3.79 (d, J = 7.2 Hz,
1H), 3.06 (t, J = 12.3 Hz, 1H), 2.79 (t, J = 11.8 Hz, 1H), 1.24 (d,
J= 6.2 Hz, 3H).
1H NMR (300 MHz, DMSO-d6) 6
12.52(s,1H),10.38(s,1H),8.56(s,1H),8.38(d, J = 6.2Hz,1H),
1-119 443 1.1 7.96(d, J= 9.4Hz,1H), 7.76-7.49(m,2H), 6.89(d, J=
6.3Hz,1H),
4.63-4.22(m,3H), 3.79(s,1H), J = 12.0Hz,1H), 2.84-
2.69(m,1H), 2.25(s,3H), 1.25(d, J = 6.2Hz,3H).
1H NMR (300 MHz, DMSO-d6) 6 12.52 (s,1H), 10.38(s,1H),
8.56(s,1H), 8.38(d, J= 6.2Hz,1H), 7.96(d, J= 9.4Hz,1H), 7.76-
1-120 443 1.1 7.49(m,2H), 6.89(d, J = 6.3Hz,1H), 4.63-4.22(m,3H),
3.79(s,1H),
J= 12.0Hz,1H), 2.84-2.69(m,1H), 2.25(s,3H), 1.25(d, J=
6.2Hz,3H).
1-123 452.90 1.825 1H NMR (400 MHz, DMSO-d6) d 10.41 (s, 1H), 8.53 (s,
1H),
8.33 (d, J = 6.2 Hz, 1H), 7.95 (d, J = 9.5 Hz, 1H), 7.72 ¨ 7.62
224
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Cmpd LCMS
S (rt, '11 NMR
mm)
(m, 1H), 6.75 (d, J = 6.4 Hz, 1H), 3.03 (d, J = 11.1 Hz, 6H), 2.34
¨2.26 (m, 1H), 2.01 ¨ 1.82 (m, 2H), 1.28 ¨ 1.08 (m, 2H), 0.96 (d,
J= 6.6 Hz, 3H).
(300MHz,DMS0 , ppm): 12.84 (s, 1H), 10.37 (s, 1H), 8.73 (s,
1H), 8.45 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.79 (s,
1H), 7.74 - 7.65 (m, 1H), 7.55 (s, 1H), 7.33 (d, J = 5.3 Hz, 1H),
1-126 430.1 1.47 4.57 (dd, J= 25.6, 12.1 Hz, 3H), 3.79 (d, J = 7.2 Hz,
1H), 3.06
(t, J = 12.3 Hz, 1H), 2.79 (t, J = 11.8 Hz, 1H), 1.24 (d, J = 6.2
Hz, 3H).
(300M1Hz,DMS0 , ppm): 12.84 (s, 1H), 10.37 (s, 1H), 8.73 (s,
1H), 8.45 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.79 (s,
1H), 7.74 - 7.65 (m, 1H), 7.55 (s, 1H), 7.33 (d, J = 5.3 Hz, 1H),
1-127 430.1 1.47 4.57 (dd, J= 25.6, 12.1 Hz, 3H), 3.79 (d, J = 7.2 Hz,
1H), 3.06
(t, J = 12.3 Hz, 1H), 2.79 (t, J = 11.8 Hz, 1H), 1.24 (d, J = 6.2
Hz, 3H).
(300MHz,DMS0 , ppm): 12.65 (s, 1H), 10.35 (s, 1H), 8.70 (s,
1H), 8.40 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.82 -
I-136 407.1 1 59 7.67 (m' 1H)' 7.61 (s, 1H), 7.43 (s, 1H), 7.23 (d,
J = 5.3 Hz, 1H),
= 4.86 (d, J = 10.2 Hz, 1H), 4.68 (d, J = 12.8 Hz, 1H), 2.72 (d, J
9.4 Hz, 2H), 2.59 (d, J= 12.0 Hz, 1H), 2.15 - 1.90 (m, 1H), 1.71
(s, 1H), 1.31 (q, J = 12.0 Hz, 1H), 0.98 (d, J = 6.5 Hz, 3H).
(300M1Hz,DMS0 , ppm): 12.64 (s, 1H), 10.36 (s, 1H), 8.70 (s,
1H), 8.41 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.70 (dd,
J = 9.4, 1.9 Hz, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 7.24 (d, J = 5.4
1-137 407.1 1.46 Hz, 1H), 4.86 (d, J= 9.1 Hz, 1H), 4.69 (d, J= 12.7
Hz, 1H), 2.73
(d, J = 9.4 Hz, 2H), 2.59 (d, J = 12.1 Hz, 1H), 2.06 (d, J = 12.9
Hz, 1H), 1.73 (s, 1H), 1.31 (q, J= 11.9 Hz, 1H), 0.99 (d, J = 6.5
Hz, 3H).
1H NMR (400 MHz, DMSO-d6) 6 10.39 (d, J = 15.2 Hz, 1H),
8.53 (d, J= 2.3 Hz, 1H), 8.31 (ddd, J = 15.4, 6.3, 2.1 Hz, 1H),
1-149 405.2 1.38 7.95 (d, J= 9.5 Hz, 1H), 7.84 - 7.54 (m, 1H), 7.40
(s, 1H), 7.03 -
6.73 (m, 2H), 3.78-3.50 (m, 2H), 2.93 (m, 1H), 2.45 - 2.0 (m,
2H), 1.58-1.35 (m, 2H), 1.02 - 0.74 (m, 3H).
1H NMR (400 MHz, DMSO-d6) 6 10.40 (s, 1H), 8.53 (s, 1H),
8.34 (dd, J = 6.3, 2.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.68 (d, J
= 9.5 Hz, 1H), 7.40 (s, 1H), 7.00 -6.74 (m, 2H), 4.50 (m, 2H),
1-154 391.2 1.31 3.11 (dt, J = 35.7, 12.4 Hz, 2H), 2.42 - 2.25 (m,
2H), 1.94 (d, J =
12.9 Hz, 1H), 1.76 (dd, J = 24.5, 13.2 Hz, 2H), 1.48 (d, J= 12.7
Hz, 1H).
1H NMR (400 MHz, DMSO-d6) 6 10.36 (s, 1H), 8.59 (s, 1H),
1-202 427.1 1.76 8.44 (d, J = 6.2 Hz, 1H), 7.97 (d, J = 9.4 Hz, 1H),
7.73 - 7.61 (m,
2H), 7.15 (s, 1H), 7.01 (d, J = 6.3 Hz, 1H), 2.75 - 2.64 (m, 3H).
225
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Cmpd LCMS
S (rt, 1H NMR
No. (ES+)
mm)
(400 MHz, DMSO-d6) 6 12.48 (d, J = 37.9 Hz, 1H), 10.38 (s,
1H), 8.55 (s, 1H), 8.38 (d, J = 6.2 Hz, 1H), 7.95 (d, J = 9.4 Hz,
1H), 7.67 (dd, J = 9.4, 2.0 Hz, 1H), 7.45 (s, 1H), 6.87 (d, J = 6.3
1-214 444.1 1.67 Hz, 1H), 4.55 (dd, J= 11.0, 2.7 Hz, 1H), 4.49-4.19 (m,
2H), 3.85
¨3.67 (m, 1H), 3.09 (t, J = 12.1 Hz, 1H), 2.85 ¨ 2.69 (m, 1H),
2.25 (s, 3H), 1.24 (d, J = 6.2 Hz, 3H).
(300 MHz, DMSO,ppm): 12.84 (s, 1H), 9.94 (s, 1H), 8.73 - 8.54
(m, 1H), 8.40 (d, J = 3.8 Hz, 1H), 7.91 - 7.70 (m, 2H), 7.53 (d, J
1-247 396.0 1.11 = 10.5 Hz, 2H), 7.26 (d, J = 4.9 Hz, 1H), 4.57 (d, J
= 32.9 Hz,
3H), 3.80 (d, J = 10.8 Hz, 1H), 3.17 - 2.63 (m, 2H), 1.26 (d, J
6.4 Hz, 3H).
(300 MHz, DMSO, ppm): 12.84 (s, 1H), 9.96 (s, 1H), 8.62 (s,
1H), 8.42 (s, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 10.6 Hz,
1-248 396.0 1.10 2H), 7.28 (s, 1H), 4.63 (d, J = 11.5 Hz, 3H), 3.81
(s, 1H), 3.23 -
2.68 (m, 2H), 1.26 (d, J = 6.0 Hz, 3H).
(300 MHz, DMSO,ppm): 12.64 (s, 1H), 9.62 (s, 1H), 8.46 (s,
1H), 8.32 (d, J = 5.3 Hz, 1H), 7.87 - 7.36 (m, 3H), 7.14 (t, J ¨
I-249 400.1 1 71 7.2 Hz' 2H)' 4.80 (dd, J = 37.2, 11.9 Hz, 2H), 3.45
(qd, J = 7.0,
= 5.1 Hz, 1H), 2.89 - 2.66 (m, 2H), 2.03 (d, J= 12.7 Hz, 1H), 1.71
(s, 2H), 1.26 (dd, J = 20.9, 8.9 Hz, 1H), 1.09 - 0.85 (m, 5H), 0.64
(s, 2H).
1H NMR (400 MHz, DMSO-d6, ppm) 12.66 (s, 1H), 9.05 (s,
1H), 8.44 (s, 1H), 8.33 (d, J = 5.3 Hz, 1H), 7.69 (d, J = 9.5 Hz,
1H), 7.64 (s, 1H), 7.45 (s, 1H), 7.15 (d, J= 5.3 Hz, 1H), 7.04 (d,
1-259 451.1 2.11 J = 9.5 Hz, 1H), 4.80 - 4.77 (m, 2H), 4.14 - 3.71 (m,
4H), 2.87 -
2.83 (m, 1H), 2.78 - 2.73 (m, 1H), 2.59 - 2.55 (m, 1H), 2.00 -
1.98 (m, 1H), 1.72- 1.70 (m, 1H), 1.34- 1.30 (m, 1H), 0.98 (d, J
= 6.5 Hz, 3H).
1H NMR (300 MHz, DMSO-d6, ppm) 12.53 (s, 1H), 9.10 (s,
1H), 8.43 (s, 1H), 8.31 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 9.6 Hz,
1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.12 (d, J= 5.3 Hz, 1H), 7.08-
1-261 451.2 1.19 7.04 (m, 1H), 4.32 - 4.08 (m, 4H), 4.02 - 3.90 (m, 3H),
3.59 -
3.56 (m, 1H), 3.15 - 3.10 (m, 1H), 1.94- 1.90 (m, 2H), 1.72 -
1.62 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H).
1H NMR (300 MHz, DMSO-d6, ppm) 12.62 (s, 1H), 8.86 (s,
1H), 8.37 (s, 1H), 8.28 (d, J = 5.3 Hz, 1H), 7.57 (d, J = 9.5 Hz,
3H), 7.10 (d, J = 5.3 Hz, 1H), 6.88 (dd, J = 9.5, 2.1 Hz, 1H), 4.76
1-271 415.0 1.15 (d, J= 11.7 Hz, 2H), 3.56 (br s, 4H), 2.76 (t, J =
12.7 Hz, 2H),
2.44 (s, 1H), 2.12 (s, 2H), 1.95 (d, J = 12.7 Hz, 1H), 1.67 (s, 1H),
1.26 (q, J= 11.7 Hz, 1H), 0.94 (d, J = 6.5 Hz, 3H).
1H NMR (400 MHz, DMSO-d6, ppm) 12.55 (s, 1H), 9.13 (s,
1-287 465.1 1.24 1H), 8.40 (s, 1H), 7.68 (d, J = 9.5 Hz, 1H), 7.56
(s, 1H), 7.40 (s,
1H), 7.10 - 7.01 (m, 2H), 4.14 (s, 4H), 4.02 (s, 1H), 3.98 (d, J =
226
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Cmpd LCMS
S (rt, 1H NMR
No. (ES+)
mm)
12.8 Hz, 2H), 3.52 (s, 1H), 3.11 (s, 1H), 2.32 (s, 3H), 1.89 (d, J=
9.3 Hz, 2H), 1.67 (s, 1H), 0.97 (d, J = 6.5 Hz, 3H).
(400 MHz, DMSO-d6. ppm) 12.67 (s, 1H), 9.06 (s, 1H), 8.39 (s,
1H), 7.67 (d, J = 9.6 Hz, 2H), 7.45 (s, 1H), 7.08 (s, 1H), 7.02 (d,
J 9.5 Hz, 1H), 4.82 (d, J 10.4 Hz, 2H), 4.07 (s, 4H),
2.77 (d,
1-288 465.1 1.23 J= 11.5 Hz, 2H), 2.55 (d, J= 17.2 Hz, 1H), 2.32 (s,
3H), 1.98 (d,
J= 12.7 Hz, 1H), 1.71 (s, 1H), 1.28 (q, J¨ 12.1 Hz, 1H), 0.98 (d,
J= 6.5 Hz, 3H).
(300 MHz, DMSO-d6, ppm) 12.62 (s, 1H), 8.86 (s, 1H), 8.37 (s,
1H), 8.28 (d, J = 5.3 Hz, 1H), 7.65 - 7.33 (m, 3H), 7.10 (d, J =
1-272 415.0 116 5.3 Hz' 1H)' 6.88 (dd, J 9.5, 2.1 Hz, 1H), 4.85 -
4.72 (m, 2H),
= 3.72 - 3.3 5(m, 4H), 2.87 - 2.73 (m, 2H), 2.57 - 2.43 (m, 1H),
2.20 - 2.03 (m, 2H), 2.01 - 1.90 (m, 1H), 1.80 - 1.63 (m, 1H),
1.32- 1.09 (m, 1H), 0.94 (d, J= 6.5 Hz, 3H).
12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57
(1H), 7.46 (1H), 6.84 (1H), 3.82 (1H), 2.83 (2H), 2.58 (2H), 2.42
1-310 429 1.392
(1H), 1.13 (3H)
1H NMR (400 MHz, DMSO-d6) d 10.50 (dd, J = 1.9, 0.9 Hz,
1H), 8.54 (s, 1H), 8.33 (d, J = 6.3 Hz, 1H), 7.95 (dd, J = 9.4, 0.9
Hz, 1H), 7.81 (dd, J¨ 9.4, 1.9 Hz, 1H), 6.73 (d, J= 6.4 Hz, 1H),
1-312 463.1 1.08 5.14 ¨ 3.91 (m, 3H), 3.37 (s, 3H), 3.22 (td, J=
10.4, 9.8, 5.1 Hz,
1H), 3.06 (d, J = 0.9 Hz, 3H), 3.02 (d, J = 0.9 Hz, 3H), 2.55 (s,
1H), 1.93 (d, J = 12.8 Hz, 1H), 1.76¨ 1.58 (m, 1H), 1.17 (q, J
11.9 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) d 12.61 (s, 1H), 10.54 (dd, J
2.0, 0.9 Hz, 1H), 8.54 (s, 1H), 8.34 (d, J = 6.3 Hz, 1H), 7.95 (dd,
J 9.4, 0.9 Hz, 1H), 7.81 (dd, J 9.4, 1.9 Hz, 1H), 7.68 (s, 1H),
1-313 424.2 1.19 7.49 (s, 1H), 6.87 (d, J = 6.3 Hz, 1H), 4.49 (d, J =
54.0 Hz, 4H),
3.11 (d, J¨ 23.8 Hz, 2H), 2.71 (d, J= 24.5 Hz, 2H), 2.16 ¨ 2.03
(m, 1H), 1.85 (d, J= 5.6 Hz, 1H), 1.79¨ 1.55 (m, 2H).
(300MHz, DMSO, ppm) 12.34 (d, J = 35.0 Hz, 1H), 10.35 (s,
1H), 8.48 (s, 1H), 8.33 (d, J = 6.3 Hz, 1H), 7.92 (d, J = 9.4 Hz,
1-314 444.0 0.93 1H), 7.65 (m, 1H), 7.36 (s, 1H), 6.79 (d, J = 6.4
Hz, 1H), 5.12 (d,
J= 4.6 Hz, 1H),4.46 (s, 1H), 3.31 (m, 1H), 3.56 (d, J¨ 4.9 Hz,
1H), 2.67 (d, J= 26.7 Hz, 3H), 2.16 (s,4H), 1.60 (s, 1H).
(300MHz, DMSO, ppm) 12.33 (d, J = 36.2 Hz, 1H), 10.35 (s,
1H), 8.48 (s, 1H), 8.33 (d, J = 6.3 Hz, 1H), 7.92 (d, J = 9.4 Hz,
1-315 444.0 0.93 1H), 7.78 - 7.25 (m, 2H), 6.79 (d, J= 6.4 Hz, 1H),
5.12 (d, J
4.5 Hz, 1H), 4.82 - 4.01 (s, 1H), 3.56 (s, 1H), 3.31 (m, 1H), 2.87 -
2.54 (m, 3H), 2.17 (m, 4H), 1.59 (s, 1H).
I 318 465 5 1.29 1H NMR (400 MHz, DMSO-d6) d 12.61 (s, 1H), 10.50 (dd, J
¨
- .
2.0, 0.9 Hz, 1H), 8.52 (s, 1H), 8.33 (d, J = 6.3 Hz, 1H), 8.17 (s,
227
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Cmpd LCMS
S (rt, 1H NMR
mm)
1H), 7.94 (dd, J = 9.4, 0.8 Hz, 1H), 7.64 (dd, J = 9.4, 1.9 Hz,
2H), 7.53 (s, 1H), 6.86 (d, J = 6.3 Hz, 1H), 4.47 (d, J = 66.6 Hz,
2H), 3.20 ¨ 3.04 (m, 2H), 2.75 (dd, J= 9.7, 5.1 Hz, 1H), 2.21 (dt,
J= 6.7, 3.4 Hz, 1H), 2.09 (dd, J = 11.2, 3.5 Hz, 1H), 1.89 ¨ 1.78
(m, 1H), 1.79¨ 1.67 (m, 1H), 1.67¨ 1.56 (m, 1H), 0.60 ¨ 0.45
(m, 2H), 0.41 (qd, J = 5.4, 2.4 Hz, 2H).
1H NMR (400 MHz, DMSO-d6) d 10.46 (dd, J = 2.0, 0.9 Hz,
1H), 8.52 (s, 1H), 8.33 (d, J = 6.3 Hz, 1H), 8.19 (s, 1H), 7.94 (dd,
J= 9.5, 0.9 Hz, 1H), 7.65 (dd, J = 9.4, 1.9 Hz, 1H), 6.73 (d, J ¨
I-319 504.2 1 23 6.4 Hz' 1H)' 4.94 ¨ 4.07 (m, 3H), 3.23 (s, 1H),
3.05 (dd, J = 13.6,
= 0.9 Hz, 6H), 2.70 ¨ 2.59 (m, 1H), 2.26 (dt, J = 6.8, 3.4 Hz, 1H),
1.94 (d, J= 12.8 Hz, 1H), 1.75 ¨ 1.57 (m, 1H), 1.17 (q, J = 12.0
Hz, 1H), 0.98 (d, J = 6.5 Hz, 3H), 0.60 ¨ 0.46 (m, 2H), 0.47 ¨
0.34 (m, 2H).
1H NMR (400 MHz, DMSO-d6) 6 12.62 (s, 1H), 10.49 (dd, J =
1.9, 0.9 Hz, 1H), 8.51 (s, 1H), 8.32 (d, J = 6.3 Hz, 1H), 7.93 (dd,
J = 9.4, 0.9 Hz, 1H), 7.72 (dd, J = 9.4, 1.9 Hz, 1H), 7.70 ¨7.41
1-320 425.1 1.09 (m, 4H), 6.86 (d, J = 6.4 Hz, 1H), 4.48 (d, J = 59.9
Hz, 2H), 3.11
(tt, J = 10.6, 4.5 Hz, 2H), 2.73 (dd, J = 9.1, 5.0 Hz, 1H), 2.14 ¨
2.05 (m, 1H), 1.83 (d, J = 13.4 Hz, 1H), 1.70 (ddd, J = 22.7,
11.5, 2.9 Hz, 1H), 1.65 ¨ 1.55 (m, 1H).
12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57
1-322 485 2.037 (1H), 7.46 (1H), 6.84 (1H), 4.72 (1H), 4.47 (4H), 3.82
(1H), 2.83
(2H), 2.58 (2H), 2.42 (1H), 1.13 (3H)
IIINMR (400 MHz, Chloroform-d) 6 9.90 (d, J = 2.3 Hz, 1H),
8.54 (s, 1H), 8.24 (d, J = 6.2 Hz, 1H), 7.73 (d, J = 9.7 Hz, 1H),
7.40 ¨ 7.34 (m, 2H), 7.23 ¨ 7.09 (m, 2H), 7.09 ¨ 7.01 (m, 2H),
1-325 477.25 1.392 6.41 (d, J= 6.2 Hz, 1H), 4.51 (s, 2H), 3.29 (dq, J
= 10.5, 5.3, 4.4
Hz, 1H), 3.05 (d, J = 13.3 Hz, 7H), 2.73 (t, J = 11.9 Hz, 1H),
2.47 (t, J = 12.4 Hz, 1H), 2.07 (d, J = 13.1 Hz, 1H), 1.31 (q, J =
12.0 Hz, 1H), 0.97 (d, J = 6.6 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) 6 10.45 (dd, J = 2.0, 0.9 Hz,
1H), 8.51 (s, 1H), 8.31 (d, J = 6.3 Hz, 1H), 7.92 (dd, J = 9.4, 0.9
Hz, 1H), 7.72 (dd, J = 9.4, 1.9 Hz, 1H), 7.63 (s, 2H), 6.73 (d, J =
1-328 464.2 1.00 6.4 Hz, 1H), 4.51 (s, 3H), 3.29 ¨ 3.16 (m, 1H), 3.06
(d, J = 0.9
Hz, 3H), 3.03 (d, J = 0.9 Hz, 3H), 2.68 ¨2.56 (m, 1H), 1.93 (d, J
= 12.6 Hz, 1H), 1.76¨ 1.59(m, 1H), 1.17 (q, J = 11.9 Hz, 1H),
0.97 (d, J= 6.5 Hz, 3H).
1H NMR (400 MHz, Chloroform-d) d 9.88 (dd, J = 2.4, 0.8 Hz,
1-329 437.90 1.857
1H), 8.56 (s, 1H), 8.26 (d, J = 6.2 Hz, 1H), 7.74 (dd, J = 9.7, 0.8
Hz, 1H), 7.50 (s, 2H), 7.41 ¨ 7.33 (m, 2H), 7.20 (dd, J = 9.6, 2.3
Hz, 1H), 7.18 ¨ 7.12 (m, 1H), 7.09 ¨ 7.04 (m, 2H), 6.40 (d, J
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S (rt, 1H NMR
No. (ES+)
mm)
6.2 Hz, 1H), 4.25 (s, 1H), 3.20 ¨2.93 (m, 2H), 1.91 ¨ 1.79 (m,
2H), 1.78 ¨ 1.63 (m, 2H), 1.60 ¨ 1.40 (m, 2H). Spectra
1H NMR (400 MHz, DMSO-d6) 6 9.11 (s, 1H), 8.41 (s, 1H), 8.30
(d, J= 5.3 Hz, 1H), 7.66 (d, J = 9.5 Hz, 1H), 7.13 (d, J = 5.3 Hz,
1H), 7.03 (dd, J 9.5, 2.1 Hz, 1H), 5.55 (d, J 57.5 Hz, 1H),
1-330 458.2 1.16 4.70 (d, J = 12.6 Hz, 2H), 4.26 (d, J = 6.7 Hz, 2H),
4.03 (ddd, J
= 34.5, 23.2, 9.1 Hz, 2H), 3.01 (d, J= 6.1 Hz, 7H), 2.65 (d, J =
14.6 Hz, 1H), 1.99 (d, J = 12.7 Hz, 1H), 1.68 (s, 1H), 1.13 (q, J
11.9 Hz, 1H), 0.94 (d, J = 6.5 Hz, 3H).
1H NMR (400 MHz, Chloroform-d) 6 10.22 (dd, J= 2.5, 1.5 Hz,
1H), 8.59 (s, 1H), 8.29 (d, J = 6.3 Hz, 1H), 7.85 ¨ 7.75 (m, 1H),
7.45 (dd, J= 9.3, 1.8 Hz, 1H), 6.45 (d, J = 6.3 Hz, 1H), 3.33 (tt, J
1-340 434.90 1.546 = 10.9, 4.4 Hz, 1H), 3.10 (d, J= 0.9 Hz, 3H), 3.07
(d, J= 0.9 Hz,
3H), 2.76 (t, J = 13.0, 10.7 Hz, 1H), 2.53 (t, J = 12.3 Hz, 1H),
2.09 (ddt, J = 12.7, 4.0, 2.1 Hz, 1H), 1.79 (d, J = 12.8 Hz, 3H),
1.42¨ 1.28 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H).
12.7 (1H), 10.36 (1H), 8.56 (1H), 8.36 (1H), 7.90 (2H), 7.42
1-352 489 0.979 (1H), 6.84 (1H), 4.42 (1H), 4.25 (1H), 3.52 (1H), 3.43
(1H), 3.11
(1H), 2.32 (1H), 1.83 (1H)
12.84 (1H), 10.36 (1H), 8.56 (1H), 8.36 (1H), 8.27 (1H), 7.90
1-353 496 1.255 (2H), 7.71 (1H), 7.63 (1H), 7.01 (1H), 6.84 (1H), 4.27
(2H), 3.72
(2H), 3.43 (2H), 2.98 (2H), 2.30 (1H)
12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57
1-362 485 1.671 (1H), 7.46 (1H), 6.84 (1H), 4.72 (1H), 4.47 (4H), 3.82
(1H), 2.83
(2H), 2.58 (2H), 2.42 (1H), 1.13 (3H)
12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57
(1H), 7.46 (1H), 6.84 (1H), 4.32 (2H), 3.39 (2H), 3.22 (2H), 2.39
1-369 469 1.059
(2H), 1.95 (1H), 0.85 (1H), 0.45 (2H), 0.04 (2H)
1H NMR (400 MHz, DMSO-d6) 6 10.42 (d, J = 38.1 Hz, 1H),
8.53 (s, 1H), 8.38 (dd, J = 15.5, 6.2 Hz, 1H), 7.95 (d, J = 9.4 Hz,
1-380 406.1 1.0 1H), 7.67 (dd, J = 9.4, 2.0 Hz, 1H), 7.27 (d, J =
43.5 Hz, 2H),
6.76 (d, J = 6.3 Hz, 1H), 3.08 (d, J = 12.7 Hz, 2H), 2.88 - 2.62
(m, 1H), 1.12 (d, J = 6.7 Hz, 3H).
1H NMR (400 MHz, Chloroform-d) d 9.87 (s, 1H), 8.54 (s, 1H),
8.23 (d, J = 6.0 Hz, 1H), 7.65 (d, J = 38.3 Hz, 2H), 7.37 (t, J
7.8 Hz, 2H), 7.15 (q, J = 9.0, 7.5 Hz, 2H), 7.05 (d, J = 8.0 Hz,
1-398 437.95 1.398 2H), 6.87 (s, 1H), 6.43 (d, J = 6.2 Hz, 1H), 4.49 (d,
J = 12.8 Hz,
1H), 4.22 (s, 1H), 3.28 (t, J = 11.6 Hz, 1H),3.11 (t, J = 12.2 Hz,
1H), 2.95 (s, 1H), 2.20 (d, J = 12.8 Hz, 1H), 1.95 ¨ 1.78 (m, 2H),
1.65 (d, J= 12.4 Hz, 1H). Spectra
1-399 437 95 1.419 1H NMR (400 MHz, DMSO-d6) d 9.77 ¨ 9.66 (m, 1H), 8.42
(d, J
.
= 21.7 Hz, 1H), 8.24 (dd, J= 12.9, 6.3 Hz, 1H), 7.80 (d, J= 9.6
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S (rt, 1H NMR
No. (ES+)
mm)
Hz, 1H), 7.54 (d, J = 5.2 Hz, 1H), 7.47 ¨ 7.29 (m, 2H), 7.21 ¨
7.13 (m, 2H), 7.13 ¨7.07 (m, 2H), 6.91 (s, 1H), 6.82 ¨ 6.65 (m,
1H), 4.35 (d, J = 73.8 Hz, 2H), 3.01 (dt, J = 32.7, 12.0 Hz, 2H),
2.83 ¨2.61 (m, 1H), 2.05 (t, J = 10.5 Hz, 1H), 1.72 (q, J = 11.7
Hz, 2H), 1.49 (d, J = 12.4 Hz, 1H). Spectra
12.84 (1H), 10.36 (1H), 8.56 (1H), 8.36 (1H), 8.27 (1H), 7.90
1-461 497 2.101 (2H), 7.71 (1H), 7.63 (1H), 6.84 (1H), 4.27 (2H), 3.72
(2H), 3.43
(2H), 2.98 (2H), 2.30 (1H)
1H NMR (400 MHz, Chloroform-d) d 10.40 (s, 1H), 8.59 (s, 1H),
8.35 (dd, J= 6.2, 1.5 Hz, 1H), 7.83 (d, J = 9.4 Hz, 1H), 7.64 (s,
2H), 7.46 (dd, J = 9.4, 1.9 Hz, 1H), 6.44 (dd, J = 6.3, 1.7 Hz,
1-476 538.85 1.469 1H), 4.29 (s, 2H), 3.79 (ddd, J = 20.2, 10.4, 4.4 Hz,
1H), 3.60 (tq,
J = 21.0, 11.1, 9.7 Hz, 1H), 2.76 ¨ 2.37 (m, 2H), 2.17 (d, J
54.3 Hz, 1H), 1.84¨ 1.53 (m, 1H), 1.22 ¨0.96 (m, 2H), 0.78 (s,
1H), 0.62 (s, 1H).
1H NMR (400 MHz, Chloroform-d) d 10.35 (s, 1H), 8.73 (s, 1H),
8.35 (s, 1H), 7.90 (d, J = 9.9 Hz, 1H), 7.64 ¨ 7.47 (m, 3H), 6.42
1-481 512.80 1.832 (s, 1H), 4.62 (s, 1H), 4.40 (d, J = 5.5 Hz, 1H), 4.29
(d, J = 22.7
Hz, 3H), 3.66 (s, 1H), 3.43 (s, 2H), 2.26 (s, 2H), 1.54 (s, 3H),
1.34 (s, 3H).
1-484 411.9 1.38 No NMR was obtained due to the limited amount.
(300 MHz, DMSO) 12.74 (s, 1H), 10.33 (s, 1H), 8.49 (s, 1H),
8.34 (d, J = 6.2 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.65 (d, J =
1-490 547.2 0.085 9.4 Hz, 2H), 7.44 (br, 1H), 6.80 (d, J = 6.4 Hz, 1H),
3.94 (br,
2H), 3.81 - 3.44 (m, 5H), 2.81 (s, 3H), 2.80-2.73 (m, 1H), 2.38-
2.16 (m, 3H), 2.05-1.93(m, 1H), 1.83-1.72 (m, 1H).
(300 MHz, DMSO) 12.74 (s, 1H), 10.32 (s, 1H), 8.49 (s, 1H),
8.33 (d, J = 6.3 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.65 (d, J =
1-495 547.2 1.65 9.5 Hz, 2H), 7.46 (br, 1H), 6.80 (d, J = 6.2 Hz,
1H), 3.93 (br,
2H), 3.71 (br, 2H), 3.63-3.51(m, 2H), 2.81 (s, 3H), 2.80-2.73 (m,
1H), 2.38-2.16 (m, 3H), 2.05-1.93(m, 1H), 1.83-1.72 (m, 1H).
1H NMR (400 MHz, Chloroform-d) 6 10.28¨ 10.15 (m, 1H),
8.37 ¨ 8.29 (m, 2H), 7.81 (d, J = 9.3 Hz, 1H), 7.49 (dd, J = 9.2,
1.8 Hz, 1H), 6.91 (d, J = 5.3 Hz, 1H), 4.92 ¨4.82 (m, 1H), 4.82 ¨
1-499 434.90 1.847 4.70 (m, 1H), 3.37 (tt, J = 10.9, 4.5 Hz, 1H), 3.18 ¨
2.99 (m, 6H),
2.78 (dd, J= 12.8, 10.7 Hz, 1H), 2.50 (t, J = 12.2 Hz, 1H), 2.15 ¨
2.04 (m, 1H), 1.80 (dq, J = 10.6, 6.9 Hz, 1H), 1.34 (q, J = 12.0
Hz, 1H), 1.04 (d, J = 6.6 Hz, 3H).
(300 MHz, Chloroform-d, ppm) 10.36 (s, 1H), 8.41 - 8.29 (m,
2H), 7.80 (d, J = 9.4 Hz, 1H), 7.59(s, 2H), 7.45 (dd, J= 9.4, 1.9
1-508 455.1 0.98 Hz, 1H), 6.93 (d, J= 5.3 Hz, 1H), 4.22 -4.01 (m, 2H),
4.01 -
3.74 (m, 3H), 3.02 (br, 1H), 2.67 (br, 1H),1.56(br, 1H), 0.52 -
0.18 (m, 4H).;
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S (rt, '11 NMR
mM)
1H Wit (400 MHz, Chloroform-d) 6 12.34 (s,1H), 10.39 (s, 1H),
8.65 (d, J = 48.3 Hz, 1H), 8.40 (d, J = 23.0 Hz, 1H), 8.04 (dd, J
1-511 540.90 1.849 = 51.1, 38.0 Hz, 2H), 7.81 ¨7.49 (m, 1H), 6.54 (s,
1H), 4.75 (s,
1H), 4.03 ¨ 3.11 (m, 5H), 3.03 (s, 1H), 1.97 (s, 7H), 1.27 (s, 4H),
0.88 (d, J = 20.3 Hz, 2H), 0.10 (s, 3H).
12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57
1-537 429 1.416 (1H), 7.46 (1H), 6.84 (1H), 3.82 (1H), 2.83 (2H), 2.58
(2H), 2.42
(1H), 1.13 (3H)
(400 MHz, DMSO-d6): 10.39 (s, 1H), 8.71 (s, 1H), 8.48 (d, J
5.2 Hz, 1H), 7.97 (d, J= 9.4 Hz, 1H), 7.72 (dd, J= 9.4, 1.9 Hz,
1H), 7.29 (d, J = 5.3 Hz, 1H), 7.17 (br, 1H), 5.00 (br, 1H), 4.36
1-543 510.2 167 (br'
1H)' 3.71 (br, 1H), 3.26-3.17(m, 1H), 3.06 (d, J = 11.4 Hz,
= 1H), 2.95 (s, 3H), 2.92 - 2.81 (m, 1H), 2.67 - 2.57 (m, 1H), 2.39
(t, J = 11.6 Hz, 1H), 1.62 (br, 1H), 1.08 (d, J = 6.6 Hz, 3H), 0.70
(q, J = 5.9 Hz, 1H), 0.50 (p, J = 4.6, 4.2 Hz, 2H), 0.42-0.31 (m,
1H).;
Example 17: GCN2 enzyme inhibition assay
[00469] Compounds were screened for their ability to inhibit GCN2 kinase
activity using a
Transcreener ADP2 fluorescence polarization assay that detects ADP levels
(BellBrook Labs,
WI). Assays were carried out in a buffer consisting of 25 mM Tris-HC1 (pH
7.5), 50 mM NaCl,
mM MgCl2 and 1 mM DTT. Final substrate concentrations were 280 tM ATP and 200
tM
peptidic substrate (H-Gly-Arg-Ser-Arg-Ser-Arg-Ser-Arg-Ser-Arg-Ser-Arg-Ser-Arg-
Ser-Arg-OH
[(RS)7], Bachem, Switzerland). Assays were carried out at 25 C in the
presence of a (typical) final
concentration of 4 nM GCN2 kinase.
[00470] An assay buffer containing GCN2 kinase and (RS)7 was prepared. 4.7 !IL
of this stock
solution was placed per well of a black, low volume, 384-well microtitre plate
(e.g. catalogue
number 3676, Corning Inc., NY). To this was added 0.65 tM of DMSO containing
serial dilutions
of the test compound (typical final concentrations of test compound were 0 to
8 The plate
was incubated for 10 minutes at 25 C prior to the addition of 4.7 tL of ATP
stock buffer to initiate
the enzyme reaction. The reaction was allowed to proceed for 1 hour at 25 C,
prior to the addition
of 10 !IL detection buffer (consisting of appropriate concentrations of ADP2
antibody and ADP
Alexa633 tracer in 1 x stop and detect buffer as supplied by BellBrook Labs).
The reaction was
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left to incubate for 1 hour at 25 C, prior to measuring the fluorescence
polarisation signal (mP) in
each well using a PHERAstar FS reader (BMG Labtech, Germany).
[00471] Fluorescence polarization values were normalized to an in plate
standard curve
consisting of various ratios of ATP to ADP in assay buffer to a final total
concentration of 280
M. 9.4 tL of each ATP:ADP ratio buffer was added to the plate along with 0.65
tL DMSO, prior
to addition of detection buffer, to mimic assay volumes and conditions. The
standard curve was
used to convert mP values obtained from test wells into percentage ATP
converted to ADP.
Percentage inhibition of enzyme activity was then calculated at each compound
dose. IC50 and
Ki(app) (using known assay and kinetic parameters) values were calculated from
percentage
inhibition data using a non-linear, tight-binding algorithm. All data analysis
was undertaken using
the Screener software package (Genedata, Switzerland).
Table 3: Enzyme activity for compounds of formula I
[00472] +++ for Ki<10 nM; ++ for Ki in 10 nM-100 nM range; and + for Ki 100 nM-
1 [tM.
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Compound GCN2 (Ki)
I-1 ++
1-2 +++
1-3 +++
1-4 ++
1-5 ++
1-6 ++
1-7 +
1-8 ++
1-9 +++
I-10 +++
I-11 ++
1-12 +++
1-13 +++
1-14 ++
1-15 +++
1-16 +++
1-17 +++
1-18 +++
1-19 ++
1-20 +++
1-21 ++
1-22 +++
1-23 +++
1-24 +++
1-25 +++
1-26 +
1-27 +++
1-28 +++
1-29 +++
1-30 +
1-31 ++
1-32 ++
1-33 ++
1-34 +++
1-35 ++
1-36 +++
1-37 +++
1-38 ++
1-39 +++
1-40 +++
1-41 +++
1-42 +++
1-43 +++
1-44 +++
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1-45 +++
1-46 ++
1-47 +++
1-48 +++
1-49 ++
1-50 +++
1-51 +++
1-52 +++
1-53 +++
1-54 ++
1-55 ++
1-56 ++
1-57 ++
1-58 ++
1-59 +
1-62 ++
1-63 +++
1-65 ++
1-66 ++
1-76 +
1-77 +
1-81 ++
1-83 ++
1-84 +
1-85 +
1-86 ++
1-87 +
1-88 +
1-89 ++
1-90 +++
1-91 ++
1-92 +++
1-93 ++
1-94 +
1-95 ++
1-96 +++
1-97 ++
1-98 ++
1-99 ++
1-100 +++
1-101 +++
1-102 +++
1-103 +++
1-104 ++
1-105 ++
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1-106 ++
1-107 +++
1-108 +++
1-109 ++
I-110 +++
I-111 ++
1-112 +++
1-113 +++
1-114 +++
1-115 +++
1-116 +++
1-117 +++
1-118 +++
1-119 +++
1-120 +++
1-137 +++
1-154 +++
1-137 +++
1-149 +++
1-202 +++
1-380 +++
1-484 +++
Table 4: Enzyme activity for compounds of formula I
[00473] +++ for IC50<10 nM; ++ for IC50 in 10 nM-100 nM range; + for IC50 100
nM-1 11.M.
Compound GCN2 (ICso)
1-122 +++
1-123 ++
1-124 +++
1-125 +++
1-126 +++
1-127 +++
1-128 ++
1-129 ++
1-130 ++
1-131
1-132 ++
1-133
1-134 ++
1-135 +++
1-136 +++
1-137 +++
1-138 ++
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1-139 +
1-140 +
1-141 +
1-142 +
1-143 ++
1-144 +
1-145 +
1-146 +
1-147 ++
1-148 +++
1-149 +++
1-150 ++
1-151 +
1-152 ++
1-153 +++
1-154 +++
1-155 +
1-156 +
1-157 +
1-158 ++
1-159 ++
1-160 +++
1-161 ++
1-162 ++
1-163 ++
1-164 ++
1-165 ++
1-166 ++
1-167 +
1-168 ++
1-169 ++
1-170 ++
1-171 ++
1-172 ++
1-173 +
1-174 ++
1-175 +++
1-176 +++
1-177 ++
1-178 +
1-179 +++
1-180 +++
1-181 ++
1-182 ++
1-183 ++
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1-184 ++
1-185 ++
1-186 +++
1-187 ++
1-188 ++
1-189 ++
1-190 +
1-191 ++
1-192 ++
1-193 +++
1-195 ++
1-196 +++
1-197 ++
1-198 +++
1-199 +++
1-200 +++
1-201 ++
1-202 +++
1-203 ++
1-204 ++
1-205 ++
1-206 ++
1-207 +
1-208 ++
1-209 ++
1-210 +
1-211 +
1-212 +
1-213 ++
1-214 +
1-217 ++
1-218 ++
1-219 ++
1-220 ++
1-221 +++
1-222 ++
1-223 +++
1-224 +
1-225 +
1-226 +
1-227 ++
1-228 +
1-229 +++
1-230 ++
1-231 +
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1-232 +
1-233 +
1-234 ++
1-235 ++
1-236 ++
1-238 ++
1-239 +
1-240 +
1-241 ++
1-242 ++
1-243 +
1-244 ++
1-245 ++
1-246 ++
1-247 +++
1-248 +++
1-249 +++
1-250 ++
1-251 ++
1-252 +
1-253 +
1-254 +
1-255 +
1-256 +
1-257 +
1-258 ++
1-259 +++
1-260 +++
1-261 +++
1-262 ++
1-263 ++
1-264 +++
1-265 ++
1-266 +++
1-267 ++
1-268 +++
1-269 ++
1-270 +++
1-271 ++
1-272 +++
1-273 +++
1-274 ++
1-275 +++
1-276 +
1-277 ++
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1-278 +++
1-279 ++
1-280 ++
1-281 ++
1-282 +
1-283 ++
1-284 ++
1-285 +
1-286 +++
1-287 ++
1-288 +++
1-289 ++
1-290 ++
1-291 ++
1-292 +
1-293 +++
1-294 +
1-295 ++
1-296 +
1-297 ++
1-298 +
1-299 +
1-300 ++
1-301 +
1-302 +++
1-303 ++
1-304 ++
1-305 +
1-307 ++
1-308 ++
1-309 +
1-310 +++
1-311 ++
1-312 +
1-313 ++
1-314 +++
1-315 +++
1-316 +++
1-317 ++
1-318 +
1-319 +
1-320 ++
1-321 ++
1-322 ++
1-323 +++
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1-324 +
1-325 +
1-326 +++
1-327 ++
1-328 +
1-329 ++
1-330 +
1-331 +
1-332 +
1-333 +
1-334 +
1-335 +
1-336 ++
1-337 +
1-338 +
1-339 ++
1-340 +++
1-341 +
1-342 ++
1-343 +
1-344 +
1-345 +
1-346 ++
1-347 +
1-348 ++
1-349 ++
1-350 +
1-351 +++
1-352 +++
1-353 +++
1-354 +++
1-355 +
1-356 ++
1-357 ++
1-358 +++
1-359 +++
1-360 +++
1-361 ++
1-362 +++
1-363 +
1-364 +
1-365 +
1-366 +++
1-367 +
1-368 +
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1-369 +++
1-370 +++
1-371 +++
1-372 +++
1-373 +++
1-374 +++
1-375 ++
1-376 ++
1-377 ++
1-378 ++
1-379 ++
1-380 +++
1-382 +
1-383 +++
1-384 +++
1-385 +++
1-386 +
1-387 +
1-388 +
1-389 ++
1-390 +++
1-391 +
1-392 +
1-393 +
1-394 +
1-395 +
1-396 ++
1-397 ++
1-398 +
1-399 ++
1-400 ++
1-401 +
1-402 +
1-403 +
1-404 ++
1-405 ++
1-406 ++
1-407 ++
1-408 ++
1-409 ++
1-410 +
1-411 +
1-412 +
1-413 +
1-414 ++
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1-415 +
1-416 ++
1-417 +
1-418 ++
1-419 ++
1-420 ++
1-421 ++
1-422 ++
1-423 +
1-424 ++
1-425 +
1-426 ++
1-427 ++
1-428 ++
1-429 +++
1-432 ++
1-433 ++
1-434 +
1-435 +++
1-436 ++
1-437 +
1-438 ++
1-439 +
1-440 +
1-441 ++
1-442 ++
1-443 ++
1-444 ++
1-445 ++
1-446 ++
1-447 ++
1-448 ++
1-449 +++
1-450 ++
1-451 ++
1-452 +
1-454 ++
1-455 ++
1-456 ++
1-457 ++
1-458 ++
1-459 +++
1-460 ++
1-461 +++
1-462 +
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1-463 ++
1-464 +
1-465 +
1-466 ++
1-467 ++
1-468 +
1-469 ++
1-470 +++
1-471 +
1-472 ++
1-473 +++
1-474 +
1-475 ++
1-476 +++
1-477 ++
1-478 ++
1-479 +
1-480 +
1-481 +++
1-482 ++
1-483 +
1-484 +++
1-485 ++
1-486 +
1-487 +
1-488 ++
1-489 ++
1-490 +++
1-491 ++
1-492 ++
1-493 ++
1-494 +
1-495 +++
1-496 +
1-497 +
1-498 ++
1-499 +++
1-500 +
1-501 +
1-502 ++
1-503 ++
1-504 +++
1-505 +
1-506 ++
1-507 +
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1-508 +++
1-509 +
1-510 +++
1-511 +++
1-512 +
1-513 +
1-514 +
1-515 +
1-516 +++
1-517 +
1-518 ++
1-519 +
1-520 ++
1-521 +++
1-522 +++
1-523 ++
1-524 ++
1-525 ++
1-526 ++
1-527 ++
1-528 ++
1-529 +++
1-530 ++
1-531 ++
1-532 ++
1-533 +++
1-534 +
1-535 +
1-536 +
1-537 +++
1-538 ++
1-539 ++
1-540 +++
1-541 +
1-542 +++
1-543 +++
1-544 +++
1-545 +++
1-546 +++
1-547 +++
1-548 ++
1-549 +
1-550 +
1-551 ++
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Example 18: GCN2 cellular inhibition assay
[00474] Compounds can be screened for their ability to inhibit intracellular
GCN2 using an
AlphaScreen assay (Perkin Elmer) to detect phosphorylation of the GCN2
substrate eIF2a in
borrelidin-treated cells. U2OS cells are plated at 5,000 cells per well in 384-
well white polystyrene
plates (Corning 3570) in McCoy's 5A media (GIBCO 26600-023) supplemented with
10% foetal
bovine serum (SAFC 12103C), Penicillin/Streptomycin solution diluted 1:100
(Sigma P0781), and
2 mM L-glutamine (Sigma G7513), and allowed to adhere overnight at 37 C in 5%
CO2.
Compounds are then added to the cell media from a final concentration of 40 M
in 4-fold serial
dilutions. Borrelidin (FluoroChem M01440) is immediately added to the wells to
a final
concentration of 1004 and the cells are incubated for lh at 37 C in 5% CO2.
After lh of treatment
with borrelidin, the media is removed, and the cells are lysed with lysis
buffer (TGR BioSceinces
TGRLB) at ambient temperature.
[00475] An AlphaScreen SureFire P-eIF2a (5er51) assay kit (Perkin Elmer
TGREIF2S) was
used to measure levels of eIF2a phosphorylated on Serine 51. Anti-
phosphorylated eIF2a Ser51
antibody-linked acceptor beads (TGR BioScience 6760617) are added to the cell
homogenate
(diluted 1:250 into a mixture of activation (TGR BioScience TGRAB) and
reaction buffer (TGR
BioScience TGREIF2S) prepared immediately before use). The plate is then
incubated for 2h at
ambient temperature in the dark. Anti-eIF2a antibody-linked donor beads (TGR
BioScience
6760617) were then added (diluted 1:100 in dilution buffer (TGR BioScience
TGRDB) prepared
immediately before use). The plate is then incubated overnight at ambient
temperature in the dark.
[00476] Plates are analyzed on an Alpha Technology-compatible PHERAstar FS
plate reader
(BMG Labtech Version 1.14) to quantify phosphorylated eIF2a Ser51 levels. The
percentage
inhibition of phosphorylated eIF2a is calculated by comparison to control
wells stimulated with
borrelidin alone. These data are plotted against concentration of compound and
IC50 are
determined using Genedata Analyzer (Genedata AG Version 12Ø3).
Table 5: Cellular activity for compounds of formula! (biomarker assay)
[00477] +++ for IC50<0.511M; ++ for IC50 in 0.5 pM-51.tM range; and + for IC50
>5 pM.
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GCN2
Compound Biomarker
(IC5o)
I-1 ++
1-2 +++
1-3 +++
1-4 ++
1-5 ++
1-6 ++
1-8 ++
1-9 +++
I-10 +++
I-11
1-12 +++
1-13 ++
1-14 ++
1-15 +++
1-16 ++
1-17 +++
1-18 +++
1-19 ++
1-20 +++
1-21 ++
1-22 +++
1-23 +++
1-24 +++
1-25 ++
1-27 +++
1-28 ++
1-29 +
1-31 ++
1-32 ++
1-33 +
1-34 +++
1-35 ++
1-36 +++
1-37 +++
1-39 +++
1-41 ++
1-42 ++
1-43 ++
1-44 +++
1-45 +++
1-46 ++
1-47 ++
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1-48 +++
1-49 +
1-50 ++
1-54 ++
1-55 ++
1-56 ++
1-57 ++
1-58 ++
1-59 +
1-62 ++
1-63 +++
1-65 ++
1-66 ++
1-76 +
1-77 +
1-81 ++
1-83 ++
1-84 +
1-85 +
1-86 ++
1-88 +++
1-90 +++
1-92 ++
1-102 +++
1-103 +++
1-104 ++
I-105 +
1-106 +
1-107 +++
1-108 +++
1-109 ++
I-110 ++
I-111 ++
1-112 ++
1-113 ++
1-114 +++
1-115 +++
1-116 ++
1-117 +++
1-118 +++
1-120 +++
1-123 +++
1-124 +++
1-125 +++
1-126 +++
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1-127 +++
1-128 +++
1-130 ++
1-134 +++
1-135 +++
1-136 +++
1-137 +++
1-138 +++
1-143 +++
1-144 +++
1-145 +++
1-146 ++
1-147 +++
1-148 +++
1-149 +++
1-150 +++
1-153 +++
1-154 +++
1-157 +++
1-159 +++
1-169 ++
1-170 +++
1-171 +++
1-172 +++
1-175 +++
1-176 +++
1-177 +++
1-179 +++
1-180 +++
1-181 ++
1-182 +++
1-183 +++
1-184 +++
1-185 +++
1-186 +++
1-191 +++
1-193 +++
1-196 +++
1-197 +++
1-198 ++
1-199 +++
1-200 +++
1-201 ++
1-202 +++
1-203 ++
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1-204 ++
1-208 +++
1-209 +++
1-213 ++
1-217 ++
1-218 ++
1-219 ++
1-220 ++
1-221 +++
1-222 +++
1-223 +++
1-224 +++
1-225 ++
1-226 ++
1-227 ++
1-232 ++
1-233 ++
1-235 +++
1-236 +++
1-238 ++
1-240 ++
1-241 ++
1-242 +
1-244 ++
1-245 ++
1-246 ++
1-247 +++
1-248 +++
1-249 +++
1-250 +++
1-251 ++
1-252 ++
1-259 +++
1-260 +++
1-261 +++
1-262 +
1-263 ++
1-266 +++
1-267 ++
1-268 ++
1-269 ++
1-270 +++
1-271 +++
1-272 +++
1-273 +++
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1-274 ++
1-275 ++
1-277 ++
1-278 +++
1-279 ++
1-280 +++
1-281 +++
1-283 ++
1-284 +
1-285 ++
1-286 ++
1-287 +++
1-288 +++
1-289 ++
1-290 ++
1-291 ++
1-293 +++
1-294 +
1-295 ++
1-297 ++
1-298 +
1-300 ++
1-301 ++
1-302 +++
1-303 ++
1-304 ++
1-307 ++
1-308 ++
1-310 +++
1-311 ++
1-313 ++
1-314 +++
1-315 +++
1-316 +++
1-317 ++
1-318 +
1-320 ++
1-321 ++
1-322 +++
1-323 ++
1-324 +
1-325 ++
1-326 +++
1-327 ++
1-329 +++
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1-339 ++
1-340 +++
1-342 +++
1-343 ++
1-344 ++
1-345 ++
1-346 +++
1-347 ++
1-348 +++
1-349 ++
1-351 +++
1-352 ++
1-353 +++
1-354 +++
1-355 ++
1-356 ++
1-357 +++
1-358 +++
1-359 +++
1-360 +++
1-361 ++
1-362 +++
1-363 ++
1-363 ++
1-364 +
1-365 ++
1-366 +++
1-368 ++
1-369 +++
1-370 +++
1-371 ++
1-372 ++
1-373 +++
1-383 ++
1-384 +++
1-385 ++
1-386 ++
1-387 ++
1-388 +
1-389 ++
1-390 +++
1-391 ++
1-392 ++
1-393 ++
1-395 ++
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1-396 +
1-397 ++
1-398 ++
1-399 ++
1-400 ++
1-401 ++
1-402 ++
1-403 ++
1-404 ++
1-405 ++
1-406 ++
1-407 ++
1-408 ++
1-409 +++
1-413 +
1-414 ++
1-416 ++
1-417 +
1-418 ++
1-419 ++
1-420 ++
1-421 +
1-422 +
1-423 +
1-424 ++
1-426 ++
1-440 +
1-441 +
1-442 ++
1-443 ++
1-444 ++
1-445 ++
1-446 ++
1-447 ++
1-448 ++
1-449 +++
1-450 +++
1-461 +++
1-464 ++
1-470 +++
1-472 +++
1-473 +++
1-476 +++
1-477 +++
1-478 +++
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1-481 +++
1-490 +++
1-491 +++
1-492 ++
1-493 +++
1-494 ++
1-495 +++
1-499 +++
1-500 ++
1-501 ++
1-502 +++
1-503 +++
1-504 +++
1-505 +
1-506 ++
1-507 ++
1-508 +++
1-510 +++
1-511 +++
1-512 ++
1-516 +++
1-517 ++
1-520 +++
1-521 +++
1-522 +++
1-523 +++
1-524 ++
1-525 ++
1-526 +++
1-527 ++
1-528 +++
1-529 +++
1-530 ++
1-531 +++
1-532 ++
1-533 +++
1-536 ++
1-537 +++
1-538 ++
1-540 +++
1-541 ++
1-543 +++
1-544 +++
1-545 +++
1-546 +++
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1-552 +++
1-553 +++
1-554 +++
1-556 ++
Example 19: 4-(2-{6-chloroimidazo[1,2-alpyridin-3-yl}pyrimidin-4-y1)-3-
methylpiperazine-
2-carboxamide, 1-484
ciN
H-0
7
N Na + N
NO¨NC¨A \-0 01¨
NH2
0 0
[00478] To a solution of 4-(246-chloroimidazo[1,2-a]pyridin-3-ylIpyrimidin-4-
y1)-3-
methylpiperazine-2-carboxamide 1-451 (49.00 mg; 0.13 mmol; 1.00 eq.) and 1-
ethoxycyclopropoxy)trimethylsilane (0.13 ml; 0.66 mmol; 5.00 eq.) in methanol
(2.50 ml; 61.72
mmol; 468.32 eq.) was added acetic acid (0.06 ml; 1.05 mmol; 8.00 eq.) and
then sodium
cyanoborohydride (66.25 mg; 1.05 mmol; 8.00 eq.). Reaction was allowed to stir
overnight at 70 C
and purified with pre-HPLC (10-90% ACN/NH4OH-H20 in 12 min) to afford 44246-
chloroimidazo[1,2-a]pyri din-3 -yl pyrimidin-4-y1)-3 -methylpiperazine-2-
carboxamide (17.6 mg,
31%) as a white solid.
Example 20: 5,5-Difluoro-1-12-(6-trifluoromethyl-imidazo11,2-alpyridin-3-y1)-
pyrimidin-4-
yll-piperidine-3-carboxylic acid amide, 1-202
)N )(N
0 0 0
N 0 + ..
F F / N NH2+ F N
OH
YN
F F F F F F
[00479] In a microwave vial containing 5,5-Difluoro-142-(6-trifluoromethyl-
imidazo[1,2-
a]pyridin-3-y1)-pyrimidin-4-y1]-piperidine-3-carboxylic acid methyl ester
(118.23 mg; 0.27 mmol;
1.00 eq.) was added ammonia 7N in Me0H (2.00 m1). The reaction was stirred at
100 C for 72h
before it was purified with pre-HPLC (10-90% ACN/0.1%NH4OH-H20 in 12 min) to
afford 5,5-
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Difluoro-142-(6-trifluoromethyl -imidazo[1,2-a]pyri din-3-y1)-pyrimidin-4-y1]-
pip eridine-3-
carboxylic acid amide (2.2 mg, 1.9%) as a white solid.
Example 21: 3-{2-1(2R,6S)-2-Methyl-6-(1H-pyrazol-4-y1)-morpholin-4-yll-
pyrimidin-4-y11-
6-trifluoromethyl-imidazo[1,2-al pyridine 1-127 and (2S,6R)-2-methyl-6-(1H-
pyrazol-4-y1)-
4-{4-16-(trifluoromethyl)imidazo[1,2-al pyridin-3-yll pyrimidin-2-
yl}morpholine 1-126
N.17CN F,N,NH N N rNH
I)C1 DIPEA FC NC-N
E
CF3 CF3 CF3 CF3
single enantiomer single
enantiomer
[00480] Step 1: 2-Methyl-6-(1H-pyrazol-4-y1)-4-{446-
(trifluoromethyl)imidazo[1,2-
a]pyridin-3-yl]pyrimidin-2-ylImorpholine. A solution of 2-
chloro-4-[6-
(trifluoromethypimidazo[1,2-a]pyridin-3-yl]pyrimidine (200 mg, 0.60 mmol, 1
equiv, 90%), 2-
methyl-6-(1H-pyrazol-4-yl)morpholine (112.0 mg, 0.60 mmol, 1 equiv, 90%) and
DIPEA (155.8
mg, 1.21 mmol, 2 equiv, 95%) in i-PrOH (10 mL, 124.30 mmol, 206.24 equiv, 95%)
was stirred
for 16 h at 100 degrees Celsius under nitrogen atmosphere. The resulting
mixture was concentrated
under vacuum. The residue was purified by silica gel column chromatography,
eluted with hexane/
Et0Ac (1:1) to afford 2-methyl-6-(1H-pyrazol-4-y1)-4-[446-
(trifluoromethyl)imidazo[1,2-
a]pyridin-3-yl]pyrimidin-2-yl]morpholine (100 mg, 34.77%) as a white solid.
[00481] Step 2: 3-{2-[(2R,65)-2-Methyl-6-(1H-pyrazol-4-y1)-morpholin-4-y1]-
pyrimidin-4-
yl }-6-trifluoromethyl-imidazo[1,2-a]pyridine and (25,6R)-2-methyl-6-(1H-
pyrazol-4-y1)-4-{446-
(trifluoromethypimidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylImorpholine. The
racemic mixture of
2-methyl-6-(1H-pyrazol-4-y1)-44446-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
yl]pyrimidin-2-
yl]morpholine was purified by Chiral-Prep-HPLC with the following conditions
(Prep-HPLC-
032): Column, Chiralpak IA, 2*25cm, 20um; mobile phase, Hex(8mmo1/L NH3.Me0H)--
HPLC
and IPA--HPLC (hold 15% IPA--HPLC in 29 min); Detector, UV 254/220nm. Two pure
compounds were obtained: Peak 1 3-{2-[(2R,65)-2-Methyl-6-(1H-pyrazol-4-y1)-
morpholin-4-y1]-
pyrimidin-4-y1}-6-trifluoromethyl-imidazo[1,2-a]pyridine 1-127, retention time
=18.029 min,
10.6mg (22%), white solid; Peak 2 (25,6R)-2-methyl-6-(1H-pyrazol-4-y1)-4-{446-
(trifluoromethypimidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylImorpholine 1-126,
retention time =
25.76 min, 12.3 mg (25%), white solid.
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Example 22: 3-{4-1(S)-4-(3-Methanesulfonyl-cyclobuty1)-3-(1H-pyrazol-4-y1)-
piperazin-1-
y11-pyrimidin-2-y11-6-trifluoromethyl-imidazo11,2-a]pyridine 1-495 and 3-{4-
1(R)-4-(3-
Methanesulfonyl-cyclobuty1)-3-(1H-pyrazol-4-y1)-piperazin-l-y11-pyrimidin-2-
y11-6-
trifluoromethyl-imidazo[1,2-a]pyridine 1-490
N \ NH NH
a N I 'IV
1,1\I
N CI HN1 1\11,1 DIPEA N N
N/" N
/-PrOH
\
CF3 CF3 CF3
N\ SFC NN riNHN
N. 1
CF3 0' CF3 o'
single enantiomer single enantiomer
[00482] Step 1: 443 -(1H-pyrazol-4-yl)piperazin-1-y1]-246-
(trifluoromethyl)imidazo[1,2-
a]pyridin-3-yl]pyrimidine. To a stirred mixture of 4-chloro-2-[6-
(trifluoromethyl)imidazo[1,2-
a]pyridin-3-yl]pyrimidine (600.00 mg, 1.808 mmol, 1.00 equiv, 90%) and 2-(1H-
pyrazol-4-
yl)piperazine (458.67 mg, 2.712 mmol, 1.50 equiv, 90%) in i-PrOH (15.00 mL,
245.293 mmol,
271.32 equiv, 95%) were added DIEA (491.98 mg, 3.616 mmol, 2.00 equiv, 95%)
dropwise at
room temperature under nitrogen atmosphere. The resulting mixture was stirred
for 3 h at 100 C
under nitrogen atmosphere. Desired product could be detected by LCMS. The
resulting mixture
was concentrated under reduced pressure. The residue was purified by silica
gel column
chromatography, eluted with CH2C12 / Me0H (8:1) to afford 443-(1H-pyrazol-4-
yl)piperazin-1-
y1]-246-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine (510 mg,
61.26%) as a light
yellow oil.
[00483] Step 2: 444-(3-methanesulfonylcyclobuty1)-3-(1H-pyrazol-4-
yl)piperazin-1-y1]-246-
(trifluoromethypimidazo[1,2-a]pyridine-3-yl]pyrimidine. To a stirred mixture
of 443-(1H-
pyrazol-4-yl)piperazin-1-y1]-246-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
yl]pyrimidine
(100.00 mg, 0.217 mmol, 1.00 equiv, 90%) and 3-methanesulfonylcyclobutan-1-one
(169.38 mg,
1.086 mmol, 5.00 equiv, 95%) in Me0H (2.50 mL, 74.121 mmol, 270.09 equiv, 95%)
were added
CH3COOH (109.83 mg, 1.737 mmol, 8.00 equiv, 95%) and NaBH3CN (57.47 mg, 0.869
mmol,
4.00 equiv, 95%) in portions at room temperature under nitrogen atmosphere.
The resulting
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mixture was stirred for 3 h at 70 C under nitrogen atmosphere. Desired
product could be detected
by LCMS. The crude product (110 mg ) was purified by Prep-HPLC with the
following conditions
(2#SHIMADZU (HPLC-01)): Column, )(Bridge Shield RP18 OBD Column, 30*150mm,5um
;
mobile phase, Water(1 OMMOL/L NH4HCO3+0.1%NH3.H20) and ACN (30% PhaseB up to
35% in 8 min); Detector, UV 254 nm. 80 mg racemic product was obtained. The
racemic product
(80) mg was resolved by Chiral-Prep-HPLC with the following conditions (Prep-
HPLC-032):
Column, CHIRAL ART Cellulose-SB, 2*25cm,5um; mobile phase, Hex(8mmo1/L
NH3.Me0H)-
and Et0H- (hold 50% Et0H- in 17 min); Detector, UV 254 nm. This resulted in
Peak 1: of 4-
[(3 S)-4-(3-methanesulfonylcyclobuty1)-3-(1H-pyrazol-4-yl)piperazin-1-y1]-246-
(trifluoromethypimidazo[1,2-a]pyridin-3-yl]pyrimidine (11.0 mg 9.08%) as a
white solid,
retention time = 4.501min, ee:99; Peak 2: 4-[(3R)-4-(3-
methanesulfonylcyclobuty1)-3-(1H-
pyrazol-4-y1)piperazin-1-y1]-246-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
yl]pyrimidine (12.1
mg, 9.17%) as a white solid, retention time = 5.529min, ee:98.
Example 23: 4-14-({6-oxaspiro12.5loctan-l-yl}methyl)-3-(1H-pyrazol-4-
y1)piperazin-1-y11-2-
16-(trifluoromethyl)imidazo11,2-al pyridin-3-y11pyrimidine 1-476
[00484] To a microwave vial containing a solution of 443-(1H-pyrazol-4-
yl)piperazin-1-y1]-2-
[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine (50.00 mg; 0.12
mmol; 1.00 eq.) and
6-oxaspiro[2.5]octane-1-carbaldehyde (84.57 mg; 0.60 mmol; 5.00 eq.) in
methanol (2.50 ml;
61.72 mmol; 640.56 eq.), was added acetic acid (0.01 ml; 0.24 mmol; 2.00 eq.)
and then sodium
cyanoborohydride (30.33 mg; 0.48 mmol; 4.00 eq.). Reaction allowed to stir
overnight at 70C.
LCMS-3 showed desired product mass with full conversion. Reaction was allowed
to cool, then
diluted with DCM. The reaction was then added drop wise to sat. NaHCO3 and
washed 3 times
with NaHCO3 and twice with brine. The organic layer was dried with anhydrous
Na2SO4, filtered,
and concentrated in vacuo. The crude was dissolved in DMSO then purified
PuriFlash PF-C18HP
15 uL 10-90% MeCN in water (0.1% Formic Acid) 14 min gradient, then 90% for 3
min. The pure
fractions were combined and lyophilized to afford the product: 444-({6-
oxaspiro[2.5]octan-1-
yl}methyl)-3-(1H-pyrazol-4-yl)piperazin-1-y1]-246-(trifluoromethyl)imidazo[1,2-
a]pyridin-3-
yl]pyrimidine (46.60 mg; 0.09 mmol)
[00485] Example 24: 4-12-methyl-4-(oxetan-3-y1)-3-(1H-pyrazol-4-yl)piperazin-l-
y11-2-16-
(trifluoromethyl) imidazo 11,2-al pyridin-3-y11 pyrimidine, 1-322
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?0
N,
'pH 0
/NH
N N N
¨N NH HOAc, NaBH(OAc)3, THF
¨N N-00
[00486] To a solution of 442-methyl-3 -(1H-pyrazol-4-
yl)piperazin-l-y1]-2- [6-
(trifluoromethypimidazo[1,2-a]pyridin-3-yl]pyrimidine (150.00 mg; 0.35 mmol;
1.00 eq.),
oxetan-3-one (30.28 mg; 0.42 mmol; 1.20 eq.) and acetic acid (210.26 mg; 3.50
mmol; 10.00 eq.)
in THF (3m1) was treated with sodium triacetoxyborohydride (742.07 mg; 3.50
mmol; 10.00 eq.)
and the mixture was stirred at room temperature for overnight. LCMS-3 showed
that the desired
product was observed. The crude product was loaded at reverse phase HPLC and
purified with
20% ACN in Water containing 0.1% NH4OH to 100% ACN in 10 minutes at the flow
rate of 60
mL/minute to provide the product 442-methyl-4-(oxetan-3-y1)-3-(1H-pyrazol-4-
yl)piperazin-1-
y1]-246-(trifluoromethyl) imidazo [1,2-a]pyridin-3-yl]pyrimidine in 16% yield.
M/z (M+H): 485;
H NMR (DMSO-d6): 12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57
(1H), 7.46
(1H), 6.84 (1H), 3.82 (1H), 2.83 (2H), 2.58 (2H), 2.42 (1H), 1.13 (3H)
Example 25: Exemplary Compounds 1-122 to 1-563.
[00487] Additional compounds were prepared using similar methodologies to
those described
in the examples above:
6-Chloro-3-(4-(2,5-dimethy1-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-
yl)imidazo[1,2-
a]pyridine, 1-122
Dimethyl(((3R,5S)-5-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
yl)pyrimidin-4-
yl)piperidin-3-yl)imino)-X6-sulfanone, 1-123
3- { 4- [(2 S,6R)-2-Methyl-6-(3 -methy1-1H-pyrazol-4-y1)-morpholin-4-yl] -
pyrimi din-2-y1{-6-
trifluoromethyl-imidazo[1,2-a]pyridine, 1-124
(2R,6 S)-2-methyl -645 -m ethy1-1H-pyrazol-4-y1)-4-(2-(6-(trifluorom ethyl)imi
daz o [1,2-a] pyri din-
3 -yl)pyrimidin-4-yl)morpholine, 1-125
(((3R,5S)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-5-
methylpiperidin-3-
yl)imino)dimethyl- X6-sulfanone, 1-128
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(2R,6S)-6-methy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-
4-
yl)morpholine-2-carboxamide, 1-129
N,N-dimethy1-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)piperidine-3-
carboxamide, 1-130
pyrrolidin-1-y1(1-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)piperidin-3-
yl)methanone, 1-131
5-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-5-azaspiro[2.5]octane-
1-carboxamide,
1-132
methyl 5-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-5-
azaspiro[2.5]octane-1-
carboxylate, 1-133
(2S,6S)-2-methy1-6-(1H-pyrazol-4-y1)-4-(4-(6-(trifluoromethyl)imidazo[1,2-
a]pyridin-3-
y1)pyrimidin-2-y1)morpholine, 1-134
(2R,6R)-2-methy1-6-(1H-pyrazol-4-y1)-4-(4-(6-(trifluoromethyl)imidazo[1,2-
a]pyridin-3-
y1)pyrimidin-2-y1)morpholine, 1-135
3-(2-((3R,5R)-3-Methy1-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-136 (after chiral separation).
3-(2-((3S,5S)-3-Methy1-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-137 (after chiral separation).
(2S,6R)-2-methy1-6-(1H-pyrazol-3-y1)-4-(4-(6-(trifluoromethyl)imidazo[1,2-
a]pyridin-3-
y1)pyrimidin-2-y1)morpholine, 1-138
3-(2-((3R,5S)-3-(1,3-dimethy1-1H-pyrazol-4-y1)-5-methylpiperidin-1-
y1)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-139
3-(2-((3S,5R)-3-(1,3-dimethy1-1H-pyrazol-4-y1)-5-methylpiperidin-1-
y1)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-140
3-(2-((3S,5S)-3-(1,3-dimethy1-1H-pyrazol-4-y1)-5-methylpiperidin-1-
yl)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-141
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3 -(2-((3R, 5R)-3 -(1,3 -dimethyl- 1H-pyrazol-4-y1)-5 -methylpiperidin-1-
yl)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-142
3 -(2-((3R, 5R)-3 -(1 -(2-methoxyethyl)-1H-pyrazol-4-y1)-5 -methylpiperidin- 1
-yl)pyrimidin-4-y1)-
6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-143
3 -(2-((3R, 5 S)-3-(1 -(2-methoxyethyl)-1H-pyrazol-4-y1)-5 -methylpiperidin- 1
-yl)pyrimidin-4-y1)-
6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-144
3-(2-((3 S,5R)-3 -(1 -(2-methoxyethyl)-1H-pyrazol-4-y1)-5 -methylpiperidin- 1 -
yl)pyrimidin-4-y1)-
6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-145
3-(2-((3 S,5 S)-3 -(1 -(2-methoxyethyl)- 1H-pyrazol-4-y1)-5 -methylpiperi din-
1 -yl)pyrimi din-4-y1)-
6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-146
(2 S, 6 S)-2-methyl-6-(5 -m ethyl- 1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)i
mi dazo [ 1,2-a]pyri din-
3 -yl)pyrimidin-4-yl)morpholine, 1-147
(3R,5 S)-5 -methyl-1 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperidine-3 -carboxamide, 1-148
-Methyl- 1 -[2-(6-trifluoromethyl-imi dazo [ 1,2-a]pyri din-3 -y1)-pyrimi din-
4-yl] -pip eri dine-3 -
carboxylic acid amide, 1-149
(S)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)morpholine-2-
carboxamide, 1-150
(R)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)morpholine-2-
carboxamide, 1-151
(R)- 1 -(4-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-2-
yl)piperidine-3 -
carboxamide, 1-152
(S)-1-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-
yl)piperidine-3-
carboxamide, 1-153
(9-1 -[2-(6-Trifluoromethyl-imidazo[ 1,2-a] pyridin-3 -y1)-pyrimidin-4-y1]-
piperidine-3 -
carboxylic acid amide, 1-154
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(2R,6R)-2-(1,3 -dimethyl- 1H-pyrazol-4-y1)-6-methy1-4-(4-(6-
(trifluoromethyl)imi dazo [ 1,2-
a]pyridin-3 -yl)pyrimidin-2-yl)morpholine, 1-155
(2 S,6 S)-2-(1,3 -dimethy1-1H-pyrazol-4-y1)-6-methyl-4-(4-(6-
(trifluoromethyl)imidazo[ 1,2-
a]pyridin-3 -yl)pyrimidin-2-yl)morpholine, 1-156
(2R,6S)-2-(1,3 -dimethyl- 1H-pyrazol-4-y1)-6-methyl -4-(4-(6-
(trifluoromethyl)imi dazo [ 1,2-
a]pyridin-3 -yl)pyrimidin-2-yl)morpholine, 1-157
(2 S,6R)-2-(1,3 -dimethyl- 1H-pyrazol-4-y1)-6-methyl -4-(4-(6-
(trifluoromethyl)imi dazo [ 1,2-
a]pyridin-3 -yl)pyrimidin-2-yl)morpholine, 1-158
(((3R,5 S)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-y1)-5-
methylpiperidin-3-
yl)imino)dimethyl-k6-sulfanone, 1-159
4-(4-(6-chl oroimi dazo [ 1,2-a]pyri din-3 -yl)pyrimi din-2-y1)-2-methy1-6-(3 -
methy1-1H-pyrazol-4-
y1)morpholine, 1-160
241 -(2-(6-chloroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-yl)piperidin-3 -
yl)acetic acid, 1-161
241 -(2-(6-chloroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-yl)piperidin-3 -
yl)acetamide, 1-162
4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-
carboxamide, 1-163
(R)- 1 -(2-(6-chloroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-yl)piperidine-3 -
carboxamide, 1-164
241 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)piperidin-3 -yl)acetic acid,
1-165
241 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)piperidin-3 -yl)acetamide,
1-166
(((3 S,5R)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3 -y1)-5-methylpyrimidin-2-y1)-
5-methylpiperidin-
3 -yl)imino)dimethyl-k6-sulfanone, 1-167
(((3 S,5R)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3 -y1)-6-methylpyrimidin-2-y1)-
5-methylpiperidin-
3 -yl)imino)dimethyl-k6-sulfanone, 1-168
dimethyl(((3 S, 5R)-5 -methyl-1 -(4-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri
din-3 -yl)pyrimi din-2-
yl)piperidin-3 -yl)imino)-k6-sulfanone, 1-169
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3-(2-((2S,5S)-2,5-dimethy1-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-170
3-(2-((2R,5R)-2,5-dimethy1-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-171
3-(2-((2S, 5 S)-2,5-dimethy1-3-(5-methy1-1H-pyrazol-4-yl)piperazin-1-
yl)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-172
3-(2-((2R, 5R)-2,5-dimethy1-3-(5-methy1-1H-pyrazol-4-yl)piperazin-1-
yl)pyrimidin-4-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-173
(S)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-y1)-5-methylpyrimidin-2-
yl)piperidine-3-
carboxamide, 1-174
(2S,6S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-2-(5-fluoro-
1H-pyrazol-4-y1)-
6-methylmorpholine, 1-175
(2R,6S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-2-(5-fluoro-
1H-pyrazol-4-y1)-
6-methylmorpholine, 1-176
(2S,6R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-6-
methylmorpholine-2-
carboxamide, 1-177
(2R,6R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-6-
methylmorpholine-2-
carboxamide, 1-178
(2S,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-y1)-2-methyl-6-(5-
methyl-1H-
pyrazol-4-yl)morpholine, 1-179
(2R,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-y1)-2-methyl-6-(5-
methyl-1H-
pyrazol-4-yl)morpholine, 1-180
(2S,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-y1)-2-methyl-6-(5-
methyl-1H-
pyrazol-4-yl)morpholine, 1-181
(2R,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-y1)-2-methyl-6-(5-
methyl-1H-
pyrazol-4-yl)morpholine, 1-182
(S)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidine-3-
carboxamide, 1-183
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6-chl oro-3 -(5 -methy1-24(3R,5 S)-3 -methyl -5 -(1H-pyrazol-4-yl)piperi din-1
-yl)pyrimi din-4-
yl)imidazo[ 1,2-a]pyridine, 1-184
6-chloro-3 -(5-methy1-24(3R,5R)-3 -methy1-5-(1H-pyrazol-4-y1)piperidin- 1 -
yl)pyrimidin-4-
yl)imidazo[ 1,2-a]pyridine, 1-185
6-chloro-3-(5-methyl-24(3 S,5 S)-3 -methy1-5-(1H-pyrazol-4-y1)piperidin- 1 -
yl)pyrimidin-4-
yl)imidazo[ 1,2-a]pyridine, 1-186
N-(1 -(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)piperidin-3 -yl)acetamide,
1-187
4-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)piperidine-4-
carboxamide, 1-188
(2 S, 6 S)-2-methyl-6-(2H-tetrazol-5 -y1)-4-(4-(6-(trifluoromethyl)imi dazo [
1,2-a]pyri din-3 -
yl)pyrimidin-2-yl)morpholine, 1-189
(2R,6R)-2-methyl-6-(2H-tetrazol-5 -y1)-4-(4-(6-(trifluoromethyl)imi dazo [ 1,2-
a]pyri din-3 -
yl)pyrimidin-2-yl)morpholine, 1-190
(((3 S, 5R)-1 -(2-(6-chloro-7-fluoroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
y1)-5-methylpiperidin-
3 -yl)imino)dimethyl-X6-sulfanone, 1-191
3-methyl-1 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)piperidine-3-
carboxamide, 1-192
3 -(4-(2-(5-(difluoromethyl)- 1H-pyrazol-4-yl)morpholino)pyrimidin-2-
y1)imidazo[ 1,2-a]pyridine-
6-carb onitril e, 1-193
6-chloro-3 -(2-((3R, 5 S)-3-methyl-5 -(1H-pyrazol-4-yl)piperidin-1 -
yl)pyrimidin-4-yl)imi dazo[ 1,2-
a]pyridine, 1-195
6-chloro-3-(2-((3R,5R)-3 -methyl-5 -(1H-pyrazol-4-yl)piperidin- 1 -yl)pyrimi
din-4-yl)imidazo[ 1,2-
a]pyridine, 1-196
6-chl oro-3 -(5 -methyl-24(3 S, 5R)-3 -methyl -5 -(1H-pyrazol-4-yl)piperi din-
1 -yl)pyrimi din-4-
yl)imidazo[ 1,2-a]pyridine, 1-197
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6-chloro-3-(2-((3 S,5R)-3 -methy1-5 -(1H-pyrazol-4-yl)piperidin-1 -
yl)pyrimidin-4-yl)imi dazo[ 1,2-
a]pyridine, 1-198
6-chloro-3-(2-((3 S,5 S)-3 -methy1-5-(1H-pyrazol-4-yl)piperidin-1 -
yl)pyrimidin-4-yl)imidazo[ 1,2-
a]pyridine, 1-199
6-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)piperidine-3-
carboxamide, 1-200
6-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)piperidine-3 -
carboxylic acid, 1-201
(2 S,6R)-4-(4-(6-chl oroimi dazo [ 1,2-a]pyri din-3 -y1)-5 -methylpyrimi din-2-
y1)-2-methyl -645 -
methy1-1H-pyrazol-4-y1)morpholine, 1-203
(2R,6 S)-4-(4-(6-chl oroimi dazo [ 1,2-a]pyri din-3 -y1)-5 -methylpyrimi din-2-
y1)-2-methyl -645 -
methy1-1H-pyrazol-4-y1)morpholine, 1-204
5, 5-Difluoro-1 42-(6-trifluoromethyl-imidazo[ 1,2-a]pyridin-3 -y1)-pyrimidin-
4-y1]-piperidine-3 -
carboxylic acid, 1-205
5-fluoro- 1 -[2-(6-trifluoromethyl-imidazo[ 1,2-a]pyridin-3 -y1)-pyrimidin-4-
y1]-piperidine-3 -
carboxylic acid, 1-206
tert-butyl 2-carb amoy1-4-(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazine- 1 -carboxyl ate, 1-207
6-chloro-3-(6-methyl-24(3 S,5 S)-3 -methy1-5-(1H-pyrazol-4-y1)piperidin- 1 -
yl)pyrimidin-4-
yl)imidazo[ 1,2-a]pyridine, 1-208
6-chloro-3 -(6-methy1-24(3R,5R)-3 -methy1-5-(1H-pyrazol-4-y1)piperidin- 1 -
yl)pyrimidin-4-
yl)imidazo[ 1,2-a]pyridine, 1-209
6-chloro-3-(6-methyl-24(3 S,5R)-3 -methyl -5 -(1H-pyrazol-4-yl)piperi din-1 -
yl)pyrimi din-4-
yl)imidazo[ 1,2-a]pyridine, 1-210
6-chloro-3-(6-methyl-24(3R,5 S)-3 -methyl -5 -(1H-pyrazol-4-yl)piperi din-1 -
yl)pyrimi din-4-
yl)imidazo[ 1,2-a]pyridine, 1-211
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tert-butyl 3 -hydroxy- 1 -(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperidine-3 -carboxylate, 1-212
3 -hydroxy-1 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a] pyridin-3 -yl)pyrimidin-4-
yl)piperidine-3 -
carboxamide, 1-213
3 -hydroxy-1 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a] pyridin-3 -yl)pyrimidin-4-
yl)piperidine-3 -
carboxylic acid, 1-214
4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-yl)piperazine-
2-carboxamide, I-
217
(2R,6R)-4-(4-(6-chl oroi mi dazo [ 1,2-a]pyri din-3 -y1)-6-methylpyrimi din-2-
y1)-2-methyl -645 -
methyl- 1H-pyrazol-4-yl)morpholine, 1-218
(S)-1 -(5 -fluoro-4-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-
2-yl)piperidine-3 -
carboxamide, 1-219
(2 S,6 S)-4-(4-(6-chloroimidazo[ 1,2-a]pyridin-3 -y1)-6-methylpyrimidin-2-y1)-
2-methy1-6-(5 -
methyl- 1H-pyrazol-4-yl)morpholine, 1-220
(2 S,6R)-4-(4-(6-chl oroimi dazo [ 1,2-a]pyri din-3 -y1)-6-methylpyrimi din-2-
y1)-2-methyl -645 -
methyl- 1H-pyrazol-4-yl)morpholine, 1-221
(2R,6 S)-4-(4-(6-chl oroimi dazo [ 1,2-a]pyri din-3 -y1)-6-methylpyrimi din-2-
y1)-2-methyl -645 -
methyl- 1H-pyrazol-4-yl)morpholine, 1-222
(R)- 1 -(5 -fluoro-4-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-2-yl)piperidine-3 -
carboxamide, 1-223
3 -(4-(3 ,3 -difluoropiperidin- 1 -yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, I-
224
2-(difluoromethyl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)morpholine, 1-225
3 -(4-(3 -fluoro-3 -methylpiperidin-1 -yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-
a]pyridine, 1-226
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(S)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)piperidine-3-carbonitrile,
1-227
1 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)azetidine-3 -carboxamide, I-
228
-fluoro- 1 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)piperidine-3 -
carboxamide, 1-229
241 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)azetidin-3 -yl)acetamide,
1-230
34443,5 -dimethylpiperazin-1-yl)pyrimidin-2-y1)-6-(trifluoromethyl)imidazo[1,2-
a]pyridine, I-
231
(S)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)morpholine-2-
carbonitrile, 1-232
(S)-6-(trifluoromethyl)-3-(4-(3 -(trifluoromethyl)piperi din- 1 -yl)pyrimi din-
2-yl)imi dazo [ 1,2-
a]pyridine, 1-233
3 -(4-(3,5 -dimethy1-4-(oxetan-3 -yl)piperazin- 1 -yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-234
6-cyclopropy1-3 -(24(3 S,5R)-3 -methyl-5 -(1H-pyrazol-4-yl)piperidin- 1 -
yl)pyrimidin-4-
yl)imidazo[ 1,2-a]pyridine, 1-235
6-cyclopropy1-3 -(2-((3R,5 S)-3-methy1-5-(1H-pyrazol-4-yl)piperidin-1-
yl)pyrimidin-4-
yl)imidazo[1,2-a]pyridine, 1-236
tert-butyl ((3 S, 5 S)-5 -hydroxy- 1 -(2-(6-(trifluoromethyl)imi dazo [1,2-
a]pyri di n-3 -yl)pyrimi din-4-
yl)piperidin-3 -yl)carbamate, 1-237
(3R,5 S)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)piperidine-3,5-diol,
1-238
(3 S,5 S)-5-amino- 1 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-yl)piperidin-
3 -ol, 1-239
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3 -(4-((3R,4R)-3 -fluoro-4-methylpiperidin-1 -yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-
a]pyridine, 1-240
3 -(hydroxymethyl)- 1 -(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperidin-4-ol, 1-241
1 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)piperidine-3 -sulfonamide, I-
242
tert-butyl ((3R,4R)- 1 -(2-(6-chl oroimi dazo [ 1,2-a]pyri din-3 -yl)pyrimi
din-4-y1)-4-
hydroxypiperi din-3 -yl)carbamate, 1-243
(((3 S,5R)-1-(4-(6,7-dichloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-y1)-5-
methylpiperidin-3-
yl)imino)dimethyl-k6-sulfanone, 1-244
4-(2-(6-(trifluoromethyl)i mi dazo [ 1,2-a]pyri din-3 -yl)pyrimi din-4-y1)- 1-
(3 ,3 ,3 -
trifluoropropyl)piperazine-2-carboxamide, 1-245
(2 S,6 S)-4-(4-(6-chloroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-2-y1)-2-methyl-
6-(1H-pyrazol-4-
yl)morpholine, 1-246
6-Chloro-3-{2-[(2S,6R)-2-methyl-6-(1H-pyrazol-4-y1)-morpholin-4-y1]-pyrimidin-
4-y1}-
imidazo[1,2-a]pyridine, 1-247
6-Chloro-3-{2-[(2R,6S)-2-methyl-6-(1H-pyrazol-4-y1)-morpholin-4-y1]-pyrimidin-
4-y1}-
imidazo[1,2-a]pyridine, 1-248
6-Cyclopropy1-3-{2-[(3R,5R)-3-methyl-5-(1H-pyrazol-4-y1)-piperidin-1-y1]-
pyrimidin-4-y1}-
imidazo[1,2-a]pyridine, 1-249
6-Cyclopropy1-3 - {2-[(3 S,5 S)-3 -methy1-5 -(1H-pyrazol-4-y1)-piperidin- 1 -
y1]-pyrimidin-4-y1}-
imidazo[ 1,2-a]pyridine, 1-250
(2R,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-y1)-2-methy1-6-
(1H-pyrazol-4-
yl)morpholine, 1-251
tert-butyl ((3R, 5R)-1 -(2-(6-chloroimidazo[ 1,2-a] pyridin-3 -yl)pyrimidin-4-
y1)-5 -methylpiperidin-
3 -yl)carbamate, 1-252
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2-hydroxy-N-((3 S, 5 S)-5 -hydroxy- 1 -(2-(6-(trifluoromethyl)imi dazo [ 1,2-
a]pyri din-3 -
yl)pyrimidin-4-yl)piperidin-3 -yl)acetamide, 1-253
2-hydroxy-N-((3 S, 5 S)-5 -hydroxy- 1 -(2-(6-(trifluoromethyl)imi dazo [ 1,2-
a]pyri din-3 -
yl)pyrimidin-4-yl)piperidin-3 -yl)propanamide, 1-254
(3R,4R)-3 -amino- 1 -(2-(6-chloroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)piperidin-4-ol, 1-255
(3R,5R)- 1 -(2-(6-chloroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-y1)-5 -
methylpiperi din-3 -amine, I-
256
N-((3 S, 5 S)-5-hydroxy- 1 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperidin-3 -y1)- 1H-pyrazole-4-carboxamide, 1-257
1 -(2-methoxyethyl)-4-(2-(6-(trifluoromethyl)i mi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazine-2-carboxamide, 1-258
6-(3,3 -difluoroazeti din- 1 -y1)-3 -(2-((3 S,5R)-3 -m ethy1-5 -(1H-pyrazol-4-
yl)piperi din- 1 -
yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine, 1-259
(R)- 1-(3 -fluoro-6-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyridin-2-
yl)piperidine-3 -
carboxamide, 1-260
643,3 -difluoroazetidin-1 -y1)-3 -(243R, 5 S)-3 -methy1-5 -(1H-pyrazol-4-
yl)piperidin- 1 -
yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine, 1-261
3 -(4-((3 S, 5R)-3 -((dimethy1(oxo)-6-su1faney1idene)amino)-5 -methylpiperidin-
1-yl)pyrimidin-2-
yl)imidazo[1,2-a]pyridine-6-carbonitrile, 1-262
1 -(oxetan-3 -y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-yl)piperazine-
2-carboxamide, 1-263
(2 S, 6 S)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)morpholine-2-carboxamide, 1-264
(2 S, 6R)-6-methyl -4-(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)morpholine-2-carboxamide, 1-265
6-chloro-3 -(4-(3 -methy1-5 -(1H-pyrazol-4-yl)piperazin-1 -yl)pyrimidin-2-
yl)imidazo[ 1,2-
a]pyridine, 1-266
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6-chl oro-3 -(4-(3 -methyl -5-(5-methy1-1H-pyrazol-4-y1)pip erazin-l-yl)pyrimi
din-2-
yl)imidazo[1,2-a]pyridine, 1-267
6-chl oro-3 -(4-(3 -methyl -5-(5-methy1-1H-pyrazol-4-y1)-4-(methyl
sulfonyl)piperazi n-1-
yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine, 1-268
(((3S,5R)-1-(2-(6,7-dichloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-5-
methylpiperidin-3-
yl)imino)dimethyl-k6-sulfanone, 1-269
(2 S,6R)-4-(4-(6-chl oro-7-fluoroimi dazo [1,2-a]pyri din-3 -yl)pyrimi din-2-
y1)-2-methyl -6-(1H-
pyrazol-4-yl)morpholine, 1-270
6-(azetidin-l-y1)-3-(2-((3 S,5R)-3 -methy1-5-(1H-pyrazol-4-y1)piperi din-l-
yl)pyrimi din-4-
yl)imidazo[1,2-a]pyridine, 1-271
6-(azetidin-l-y1)-3-(2-((3R,5R)-3-methy1-5-(1H-pyrazol-4-y1)piperidin-1-
y1)pyrimidin-4-
y1)imidazo[1,2-a]pyridine, 1-272
(2R,6 S)-4-(4-(6-chl oro-7-fluoroimi dazo [1,2-a]pyri din-3 -yl)pyrimi din-2-
y1)-2-methy1-6-(1H-
pyrazol-4-yl)morpholine, 1-273
(2R,6R)-4-(4-(6-chl oro-7-fluoroimi dazo [1,2-a]pyri din-3 -yl)pyrimi din-2-
y1)-2-methy1-6-(1H-
pyrazol-4-yl)morpholine, 1-274
(2 S,6 S)-4-(4-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-y1)-2-
methyl -6-(1H-
pyrazol-4-yl)morpholine, 1-275
1-(4-(2-(6-chl oroimi dazo [1,2-a]pyri din-3 -yl)pyri mi din-4-y1)-2-methy1-6-
(3 -methy1-1H-pyrazol-
4-yl)piperazin-l-yl)ethan-l-one, 1-276
1-(4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-2-methy1-6-(1H-
pyrazol-4-
yl)piperazin-l-yl)ethan-l-one, 1-277
(S)-1-(5-fluoro-2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)piperidine-3-
carboxamide, 1-278
6-chl oro-3 -(6-methoxy-2-((3R,5R)-3 -methyl-5 -(1H-pyrazol-4-yl)piperi din-l-
yl)pyri mi din-4-
yl)imidazo[1,2-a]pyridine, 1-279
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6-chloro-3 -(6-methoxy-2-((3R, 5 S)-3-methy1-5-(1H-pyrazol-4-yl)piperidin-1-
yl)pyrimidin-4-
yl)imidazo[1,2-a]pyridine, 1-280
6-chloro-3-(6-methoxy-2-((3 S,5 S)-3 -methy1-5 -(1H-pyrazol-4-yl)piperidin- 1 -
yl)pyrimidin-4-
yl)imidazo[ 1,2-a]pyridine, 1-281
(S)-1 -(5 -fluoro-2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-
4-yl)piperidine-3 -
carboxamide, 1-282
N-((1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-
yl)methyl)-N-
methylmethanesulfonamide, 1-283
241 -(2-(6-chloroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-yl)piperidin-3 -y1)-
2-methylpropanoic
acid, 1-284
tert-butyl 6-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-2,6-
diazaspiro[3 5]nonane-2-
carb oxyl ate, 1-285
4-(2-(6-chloroimidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)- 1 -
cyclopropylpiperazine-2-
carboxamide, 1-286
6-(3,3 -difluoroazeti din- 1 -y1)-3 -(6-methyl -24(3 S,5R)-3 -methyl -5 -(1H-
pyrazol-4-yl)piperi din- 1 -
yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine, 1-287
6-(3,3 -difluoroazeti din- 1 -y1)-3 -(6-methyl -24(3R,5R)-3 -methy1-5 -(1H-
pyrazol-4-yl)piperi din- 1 -
yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine, 1-288
(((3 S,5R)-1-(2-(6-bromoimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-5-
methylpiperidin-3-
yl)imino)dimethyl-M-sulfanone, 1-289
dimethyl(((3 S, 5R)-5 -methyl- 1 -(2-(6-(trifluoromethoxy)imi dazo [ 1,2-
a]pyri din-3 -yl)pyrimi din-4-
yl)piperidin-3 -yl)imino)-M-sulfanone, 1-290
dimethyl(((3 S, 5R)-5 -methyl- 1 -(2-(6-(di fluoromethoxy)imi dazo [ 1,2-a]
pyri din-3 -yl)pyrimi din-4-
yl)piperidin-3 -yl)imino)-M-sulfanone, 1-291
tert-butyl 6,6-dimethy1-8-(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-
3 -yl)pyrimi di n-4-y1)-5 -
oxa-2, 8-diazaspiro[3 .5 ]nonane-2-carboxylate, 1-292
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(2R,6S)-2-methy1-6-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethoxy)imidazo[1,2-
a]pyridin-3-
yl)pyrimidin-4-yl)morpholine, 1-293
6,6-dimethy1-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
y1)-5-oxa-2,8-
diazaspiro[3.5]nonane, 1-294
(R)-6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-2,6-
diazaspiro[3.5]nonan-1-one, 1-295
(S)-6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-2,6-
diazaspiro[3.5]nonan-1-one, 1-296
1-(1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-
yl)cyclopropane-1-
carboxylic acid, 1-297
2-(4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-
yl)acetic acid, 1-298
6-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-2,6-
diazaspiro[3.5]nonane, 1-299
(((3S,5R)-1-(2-(6-cyclopropylimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-5-
methylpiperidin-3-
yl)imino)dimethyl-6-sulfanone, 1-300
6-chloro-3-(4-(3-methy1-4-(methylsulfony1)-5-(1-(methylsulfony1)-1H-pyrazol-4-
y1)piperazin-1-
y1)pyrimidin-2-y1)imidazo[1,2-a]pyridine, 1-301
1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-5-(3-methyl-1H-
pyrazol-4-
yl)piperidin-3-ol, 1-302
1-(1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-
yl)cyclopropane-1-
carboxamide, 1-303
6,6-dimethy1-2-(methylsulfony1)-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-
3-y1)pyrimidin-
4-y1)-5-oxa-2,8-diazaspiro[3.5]nonane, 1-304
246,6-dimethy1-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)morpholin-
2-yl)methoxy)-N,N-dimethylacetamide, 1-305
(3 S,5R)-5-(5-methy1-1H-pyrazol-4-y1)-1-(2-(6-(trifluoromethyl)imidazo[1,2-
a]pyridin-3-
y1)pyrimidin-4-y1)piperidin-3-ol, 1-307
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(3R,5 S)-5 -(5 -methy1-1H-pyrazol-4-y1)- 1 -(2-(6-(trifluoromethyl)imidazo[
1,2-a]pyridin-3 -
yl)pyrimidin-4-yl)piperidin-3 -ol, 1-308
241 -(2-(6-chloroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-yl)piperidin-3 -y1)-
2-
methylpropanamide, 1-309
3 -(4-((3R)-2-methyl-3 -(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-310
1 -cycl opropy1-4-(2-(6-(trifluoromethyl)imi dazo [
pyri din-3 -yl)pyrimidin-4-yl)piperazine-2-
carboxamide, 1-311
dimethyl(((3R, 5 S)-5 -methyl- 1 -(2-(6-(m ethyl sulfonyl)imi dazo [ pyri
din-3 -yl)pyrimi din-4-
yl)piperidin-3 -yl)imino)-X6-sulfanone, 1-312
3 -(4-(3 -(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-y1)-6-
(methylsulfonyl)imidazo[1,2-
a]pyridine, 1-313
(3 S,5 S)-5 -(3 -Methy1-1H-pyrazol-4-y1)-142-(6-trifluoromethyl-imidazo[1,2-
a]pyridin-3 -y1)-
pyrimidin-4-y1]-piperidin-3 -ol 1-314.
(3R, 5R)-5 -(3 -Methyl- 1H-pyrazol-4-y1)- 1 -[2-(6-trifluoromethyl-imi dazo [
pyri din-3 -y1)-
pyrimidin-4-y1]-piperidin-3 -ol 1-315
(3 S,5 S)- 1 -(4-(6-chloroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-2-y1)-5-
hydroxypiperidine-3 -
carboxamide, 1-316
(((3 S,5R)-1-(2-(6-bromo-7-fluoroimidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)-5
-methylpiperidin-
3 -yl)imino)dimethyl-X6-sulfanone, 1-317
3 -(4-(3 -(1H-pyrazol-4-yl)piperidin-1 -yl)pyrimidin-2-y1)-N-
cyclopropylimidazo[ 1,2-a]pyridine-
6-sulfonamide, 1-318
N-cyclopropyl -3 -(4-((3R, 5 S)-3 -((dimethyl(oxo)-X6-sulfaneyli dene)amino)-5
-methylpi peri din- 1 -
yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine-6-sulfonamide, 1-319,
3 -(4-(3 -(1H-pyrazol-4-yl)piperidin-1 -yl)pyrimidin-2-yl)imidazo[ 1,2-
a]pyridine-6-sulfonamide, I-
320
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3 -(4-(2-methyl-3 -(5 -methy1-1H-pyrazol-4-y1)piperazin- 1 -yl)pyrimi din-2-
y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-321
(R)- 1 -cyclopropy1-4-(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazine-2-carboxamide, 1-323
(S)-1-cyclopropy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
yl)pyrimidin-4-
yl)piperazine-2-carboxamide, 1-324
dimethyl({ [(3 S,5R)-5-methy1-1-(2-{ 6-phenoxyimidazo[1,2-a]pyridin-3 -y1}
pyrimidin-4-
yl)piperidin-3-yl]imino})-k6-sulfanone 1-325
3 -(443 -(1H-pyrazol-4-yl)piperidin-1 -yl)pyrimidin-2-y1)-6-bromo-7-
fluoroimidazo[ 1,2-
a]pyridine, 1-326
N-(1 -(4-(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyri din-3 -yl)pyrimidin-4-
yl)morpholin-2-
yl)ethyl)methanesulfonamide, 1-327
3 -(4-((3R, 5 S)-3 -((dimethyl (oxo)-k6-sulfaneylidene)amino)-5-methylpiperi
din-1 -yl)pyrimi din-2-
yl)imidazo[ 1,2-a]pyridine-6-sulfonamide, 1-328
2-{ 6-phenoxyimidazo[1,2-a]pyridin-3 -y1} -443 -(1H-pyrazol -4-yl)piperidin- 1
-yl]pyrimidine I-
329
(((3 S,5R)-1-(2-(6-(3 -fluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-y1)-5-
methylpiperi din-3 -yl)imino)dimethyl-k6-sulfanone, 1-330
6-methy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)morpholine-2-
carbonitrile, 1-331
3 -methyl-5 -(1 -methy1-4-(2-(6-(trifluorom ethypimi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazin-2-y1)- 1,2,4-oxadiazole, 1-332
3 -(4-(3,3 -dimethy1-4-(2,2,2-trifluoroethyl)piperazin- 1 -yl)pyrimi din-2-y1)-
6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-333
3 -(443,3 -dimethylpiperazin-1-yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[1,2-a]pyridine, I-
334
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3 -(4-(4-(2-methoxyethyl)-3 , 5 -dimethylpiperazin- 1 -yl)pyrimi din-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-335
1 -(2,2-dimethy1-4-(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-yl)piperazin-
1 -yl)ethan- 1 -one, 1-336
3 -(4-(3 -(5 -methy1-4H- 1,2,4-tri azol-3 -yl)pip erazin- 1 -yl)pyrimi din-2-
y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-337
8-(2-(6-(trifluoromethyl)i mi dazo [ 1,2-a]pyri din-3 -yl)pyrimi din-4-
yl)octahydropyrazino [2, 1 -
c] [1,4]thiazine 2,2-dioxide, 1-338
3 -(4-(3,3 -dimethy1-4-(methyl sulfonyl)piperazin- 1 -yl)pyrimi din-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-339
(((3 S,5R)-1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)-
5 -
methylpiperi din-3 -yl)imino)dimethyl-k6-sulfanone, 1-340
(2 S,6 S)-4-(2-(6-cyclopropy1-7-fluoroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
y1)-2-methy1-6-(3 -
methy1-1,2,4-oxadiazol-5-yl)morpholine, 1-341
dimethyl(((3R,5R)-5 -(5 -methyl- 1H-pyrazol-4-y1)- 1 -(2-(6-(trifluorom
ethypimi dazo [ 1,2-
a] pyridin-3 -yl)pyrimidin-4-yl)piperidin-3 -yl)imino)-k6-sulfanone, 1-342
(2R,6R)-2-methyl-6-(5 -methyli soxazol-4-y1)-4-(2-(6-(trifluoromethyl)imi dazo
[ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)morpholine, 1-343
dimethyl(((3 S, 5R)-5 -(5 -methyl- 1H-pyrazol -4-y1)- 1 -(2-(6-
(trifluoromethyl)imi dazo [ 1,2-
a] pyridin-3 -yl)pyrimidin-4-yl)piperidin-3 -yl)imino)-k6-sulfanone, 1-344
(2 S,6 S)-2-methy1-6-(5 -methyli soxazol-4-y1)-4-(2-(6-
(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-yl)morpholine, 1-345
(2 S, 6R)-2-methyl -6-(5 -methyli soxazol-4-y1)-4-(2-(6-(trifluoromethyl)imi
dazo [ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)morpholine, 1-346
(2R,6S)-2-methy1-6-(5 -methyli soxazol-4-y1)-4-(2-(6-(trifluoromethyl)imi dazo
[ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)morpholine, 1-347
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3-(4-(4-(1-ethoxycyclopropy1)-2-methy1-3-(1H-pyrazol-4-y1)piperazin-1-
y1)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[1,2-a]pyridine, 1-348
(R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-1-
cyclopropylpiperazine-2-
carboxamide, 1-349
(s)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-1-
cyclopropylpiperazine-2-
carboxamide, 1-350
3-(4-(3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[1,2-
a]pyridine, 1-351
3-(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
yl)pyrimidin-4-
yl)piperazin-1-yl)propane-1,2-diol, 1-352
4-((2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
yl)pyrimidin-4-
yl)piperazin-1-yl)methyl)oxazole, 1-353
3-(4-(3-(1H-pyrazol-4-y1)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-
y1)pyrimidin-2-y1)-
6-(trifluoromethyl)imidazo[1,2-a]pyridine, 1-354
6-(trifluoromethyl)-3-(4-(3-(3-(trifluoromethyl)-1H-pyrazol-1-y1)piperidin-1-
y1)pyrimidin-2-
y1)imidazo[1,2-a]pyridine, 1-355
3-(4-(3-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[1,2-
a]pyridine, 1-356
3-(4-(3-fluoro-5-(3-methy1-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[1,2-a]pyridine, 1-357
2-methy1-6-(3-methy1-1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-
a]pyridin-3-
y1)pyrimidin-4-y1)morpholine, 1-358
(2S,6R)-4-(2-(7-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-
4-y1)-2-
methy1-6-(3-methy1-1H-pyrazol-4-y1)morpholine, 1-359
(2R,6R)-4-(2-(7-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-
4-y1)-2-
methy1-6-(3-methy1-1H-pyrazol-4-y1)morpholine, 1-360
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3 -(4-((2S,3R)-2-methyl-4-(oxetan-3 -y1)-3 -(1H-pyrazol-4-yl)piperazin- 1 -
yl)pyrimi din-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-361
4- [(2R, 3 S)-2-methyl-4-(oxetan-3 -y1)-3 -(1H-pyrazol-4-yl)pip erazin- 1 -yl]
-2- [6-
(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl]pyrimidine, 1-362
3 -(4-((2R,3R)-2-methy1-4-(oxetan-3 -y1)-3 -(1H-pyrazol-4-yl)piperazin- 1 -
yl)pyrimi din-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-363
3-(4-((2S,3 S)-2-methy1-4-(oxetan-3 -y1)-3 -(1H-pyrazol-4-yl)piperazin-1 -
yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-364
3 -(4-(2 S,3R)-2-m ethyl -3 -(5 -methyl- 1H-pyrazol-4-y1)-4-(oxetan-3 -
yl)piperazin- 1 -yl)pyrimi din-
2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-365
3 -(4-(2R,3 S)-2-methyl-3 -(5 -methyl- 1H-pyrazol-4-y1)-4-(oxetan-3 -
yl)piperazin- 1 -yl)pyrimi din-
2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-366
3-(4-(2S,3 S)-2-methyl-3 -(5 -methyl - 1H-pyrazol-4-y1)-4-(oxetan-3 -
yl)piperazin- 1 -yl)pyrimi din-
2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-367
3 -(4-(2R,3R)-2-methyl-3 -(5 -methyl- 1H-pyrazol-4-y1)-4-(oxetan-3 -
yl)piperazin- 1 -yl)pyrimi din-
2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-368
444-(cyclopropylmethyl)-3 -(1H-pyrazol-4-yl)piperazin- 1 -y1]-246-
(trifluoromethyl)imidazo[ 1,2-
a]pyridin-3 -yl]pyrimidine, 1-369
3 -(44443 -oxabicyclo[3 . 1 .0]hexan-6-yl)methyl)-3 -(1H-pyrazol-4-
yl)piperazin-1-yl)pyrimidin-2-
y1)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, 1-370
3 -(4-(441H-imidazol-2-yl)methyl)-3 -(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-
2-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-371
3 -(44442-methyl- 1 H-imidazol-5 -yl)methyl)-3 -(1H-pyrazol-4-yl)piperazin- 1 -
yl)pyrimidin-2-
y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-372
3 -(4-(442-(tert-buty1)-1H-imidazol-5-yl)methyl)-3 -(1H-pyrazol-4-yl)piperazin-
1 -yl)pyrimi din-
2-y1)-6-(trifluoromethypimidazo[1,2-a]pyridine, 1-373
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3-(4-(4-(oxetan-3-ylmethyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-y1)-
6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-374
(2R,6R)-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-2-
methyl-6-(3-
methyl-1,2,4-oxadiazol-5-yl)morpholine, 1-375
(((3S,5R)-1-(2-(6-cyclopropy1-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
y1)-5-
methylpiperidin-3-y1)imino)dimethy1-X6-su1fanone, 1-376
6-cyclopropy1-7-fluoro-3-(4-(3-fluoro-5-(5-methy1-1H-pyrazol-4-yl)piperidin-1-
yl)pyrimidin-2-
yl)imidazo[1,2-a]pyridine, 1-377
4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-3-
methylpiperazine-2-
carboxamide, 1-378
3-(4-(3-methy1-4-(1H-pyrazol-1-yl)piperidin-1-yl)pyrimidin-2-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-379
3-methy1-4-{246-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-
ylIpiperazine-2-
carboxamide, 1-380
(1-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)piperidin-3-y1)-1H-1,2,3-
triazol-4-yl)methanol, 1-382
3-(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
yl)pyrimidin-4-
yl)piperazin-1-yl)cyclobutan-1-01, 1-383
3-(4-(4-((l-methy1-1H-pyrazol-4-y1)methyl)-3-(1H-pyrazol-4-y1)piperazin-l-
y1)pyrimidin-2-y1)-
6-(trifluoromethyl)imidazo[1,2-a]pyridine, 1-384
3-(4-(441H-imidazol-5-yl)methyl)-3-(1H-pyrazol-4-y1)piperazin-1-y1)pyrimidin-2-
y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-385
tert-butyl
8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-5-oxa-2,8-
diazaspiro[3.5]nonane-2-carboxylate, 1-386
tert-butyl
6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-2,6-
diazaspiro[3.5]nonane-2-carboxylate, 1-387
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tert-butyl 9,9-dimethy1-8-(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-
3 -yl)pyrimi di n-4-y1)-5 -
oxa-2,8-diazaspiro[3 .5]nonane-2-carboxylate, I -388
4-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)- 1 -
cyclopropylpiperazine-2-
carboxamide, 1-389
(3 -(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -yl)cycl obutyl)methanol, 1-390
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(1 sopropyl- 1H-pyrazol-4-yl)methanone, 1-391
3 -(4-(4-cycl opropy1-3 ,5 -dimethylpiperazin- 1 -yl)pyrimi din-2-y1)-6-
(trifluoromethyl)imi dazo [ 1,2-
a]pyridine, 1-392
2-(2,6-dimethy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-
4-yl)piperazin-1-
yl)acetonitrile, 1-393
N-(((1R,4 S)-2-(2-(6-(difluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
y1)-2-
azabicyclo[2 .2.2] octan-6-yl)methyl)methanesulfonamide, 1-394
6-(2-(6-(difluoromethyl)imi dazo [ 1,2-a]pyri din-3 -yl)pyrimidin-4-y1)-2-
(methylsulfony1)-2,6-
diazaspiro[3 .5]nonane, 1-395
8-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)-6,6-
dimethy1-2-
(methyl sulfony1)-5 -oxa-2,8-diazaspiro[3 .5 ]nonane, 1-396
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(cyclopropyl)methanone, 1-397
2-{6-phenoxyimidazo[1,2-a]pyridin-3 -y1} -4-[(3R)-3 -(1H-pyrazol-4-
yl)piperidin- 1 -
yl]pyrimidine 1-398
2-{6-phenoxyimidazo[1,2-a]pyridin-3 -y1} -4-[(3 S)-3 -(1H-pyrazol-4-
yl)piperidin-1-
yl]pyrimidine 1-399
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin-1-y1)(2,2-difluorocyclopropyl)methanone, 1-400
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(cis-2,6-dimethy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-yl)piperazin-
1 -y1)(1 -i sopropy1-1H-pyrazol-3 -yl)methanone, 1-401
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(3,3 -difluorocyclobutyl)methanone, 1-402
cyclopropyl(cis-2,6-dimethy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -yl)methanone, 1-403
N-((R)- 1 -((S)-4-(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-yl)morpholin-2-
yl)ethyl)methanesulfonamide, 1-404
N-((S)-1-((R)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)morpholin-2-
yl)ethyl)methanesulfonamide, 1-405
N-((R)- 1 -((R)-4-(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)morpholin-2-
yl)ethyl)methanesulfonamide, 1-406
N-((S)-1 -((S)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-
4-yl)morpholin-2-
yl)ethyl)methanesulfonamide, 1-407
3 -(4-((3R, 5 S)-3 -methy1-5 -(5 -methy1-2H-1,2,3 -tri azol-4-yl)piperidin- 1 -
yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-408
3-(4-((3 S,5R)-3 -methy1-5 -(5 -methy1-2H-1,2,3 -tri azol-4-yl)piperidin- 1 -
yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-409
3 -(4-(ci s-3 ,5 -dimethy1-4-(2,2,2-trifluoroethyl)piperazin- 1 -yl)pyrimi din-
2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-410
tert-butyl 3 -(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-y1)-3,9-
diazabicyclo[3 .3 . 1 ]nonane-9-carboxylate, 1-411
8-(2-(6-(trifluoromethyl)i mi dazo [ 1,2-a]pyri din-3 -yl)pyrimi din-4-y1)-5 -
oxa-2, 8-
diazaspiro[3 .5]nonane, 1-412
6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)-2,6-
diazaspiro[3 .5]nonane,
1-413
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1 -(ci s-2,6-dimethy1-4-(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin-1-yl)ethan-1 -one, 1-414
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin-1 -y1)(1 -(2-hydroxyethyl)- 1H-pyrazol-4-yl)methanone, 1-415
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin-1 -y1)(1 -(2-methoxyethyl)- 1H-pyrazol-4-yl)methanone, 1-416
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin-1 -y1)(1 -(oxetan-3 -y1)- 1H-pyrazol-4-yl)methanone, 1-417
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin-1 -y1)(1 -methyl- 1H-pyrazol-4-yl)methanone, 1-418
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin-1 -y1)(1 -methyl- 1H-pyrazol-5 -yl)methanone, 1-419
1 -(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)i mi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazin-1 -y1)-2-hydroxypropan- 1-one, 1-420
1 -(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)i mi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazin-1 -y1)-2-hydroxyethan-1 -one, 1-421
1 -(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)i mi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazin-1 -y1)-3 -(1H-imidazol-1 -yl)propan-1 -one, 1-422
1 -(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)i mi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazin-1 -y1)-3 -(3 , 5 -dimethyl- 1H-pyrazol-1 -yl)propan- 1-one, 1-423
(S)-4-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-1-
cyclopropylpiperazine-
2-carboxamide, 1-424
(R)-4-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)- 1 -
cyclopropylpiperazine-2-carboxamide, 1-425
6-chloro-7-fluoro-3-(4-(3 -fluoro-5 -(5 -methy1-1H-pyrazol-4-y1)piperi din-1 -
yl)pyrimi din-2-
yl)imidazo[ 1,2-a]pyridine, 1-426
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4-(2-(6-cyclopropy1-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-3-
methylpiperazine-2-
carboxamide, 1-427
(2 S,6 S)-4-(2-(6-cyclopropy1-7-fluoroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
y1)-2-methy1-6-(5-
methy1-1H-pyrazol-4-y1)morpholine, 1-428
(2 S,6R)-4-(2-(6-cyclopropy1-7-fluoroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
y1)-2-methy1-6-(5-
methy1-1H-pyrazol-4-y1)morpholine, 1-429
1 -(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)i mi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazine-1 -carbonyl)cyclopropane-1 -carbonitrile, 1-432
(R)- 1 -(4-(4-(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-
yl)piperazin-2-y1)-
1H-pyrazol e- 1 -carb onyl)cycl propane- 1 -carb onitrile, 1-433
(2R,3R)-3 -methyl-4-(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazine-2-carboxamide, 1-434
(2 S, 3 S)-3-methy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
yl)pyrimidin-4-
yl)piperazine-2-carboxamide, 1-435
N-(((2R,3 S)-3 -methyl -4-(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazin-2-yl)methyl)methanesulfonamide, 1-436
(3,3 -difluorocyclobutyl)(ci s-2,6-dimethyl -4-(2-(6-(trifluoromethyl)imi dazo
[ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)piperazin- 1 -yl)methanone, 1-437
(2,2-difluorocycl opropyl)(ci s-2,6-dimethy1-4-(2-(6-(trifluoromethyl)imi dazo
[ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)piperazin- 1 -yl)methanone, 1-438
3 -(4-(ci s-3 ,5 -dimethy1-4-(methyl sulfonyl)piperazin- 1 -yl)pyrimi din-2-
y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-439
(1 -cycl opropyl - 1H-pyrazol-3 -y1)(ci s-2,6-dimethy1-4-(2-(6-(trifluorom
ethypimi dazo [ 1,2-
a]pyridin-3 -yl)pyrimidin-4-yl)piperazin- 1 -yl)methanone, 1-440
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin-1 -y1)(1,2, 5 -oxadiazol-3 -yl)methanone, 1-441
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(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin-1 -y1)(2H- 1,2,3 -triazol-4-yl)methanone, 1-442
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(oxazol-4-yl)methanone, 1-443
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(isoxazol-4-yl)methanone, 1-444
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(1H-imidazol-4-yl)methanone, 1-445
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin-1 -y1)(1 -methyl- 1H-imidazol-4-yl)methanone, 1-446
2-(methyl sulfony1)-8-(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-y1)-5 -oxa-
2, 8-diazaspiro[3 .5]nonane, 1-447
2-(methyl sulfony1)-6-(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-y1)-2, 6-
diazaspiro[3 .5]nonane, 1-448
3 -(443 -(1H-pyrazol-4-y1)-4-(3,3,3 -trifluoropropyl)piperazin- 1 -
yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-449
3 -(4-(4-(3,4-difluorobenzy1)-3 -(1H-pyrazol-4-yl)piperazin- 1 -yl)pyrimi din-
2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a] pyridine, 1-450
4424 6-chloroimidazo[1,2-a]pyridin-3 -ylIpyrimidin-4-y1)-3 -methylpiperazine-2-
carboxamide, I-
451
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(2-methoxypyri din-4-yl)methanone, 1-452
(2R,3 S)-4-(2-(6-cyclopropy1-7-fluoroimidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-
y1)-3 -
methylpiperazine-2-carboxamide, 1-454
4-(2-(6-cyclopropy1-7-fluoroimidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)-3 -
methylpiperazine-2-
carboxamide, 1-455
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3 -(4-(3 -(1H-pyrazol-4-y1)-4-(tetrahydro-2H-pyran-4-yl)piperazin- 1 -yl)pyri
mi din-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-456
3 -(4-(4-(4-fluorobenzy1)-3 -(1H-pyrazol-4-yl)piperazin- 1 -yl)pyrimi din-2-
y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-457
3 -(4-(4-(3 -fluorobenzy1)-3 -(1H-pyrazol-4-yl)piperazin- 1 -yl)pyrimi din-2-
y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-458
3 -(4-(4-(2-fluorobenzy1)-3 -(1H-pyrazol-4-yl)piperazin- 1 -yl)pyrimi din-2-
y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-459
3 -(4-(4-(4,4-difluorocyclohexyl)-3 -(1H-pyrazol-4-yl)piperazin- 1 -yl)pyrimi
din-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-460
4- { 4-[(1,2,5 -oxadiazol-3 -yl)methy1]-3 -(1H-pyrazol-4-yl)piperazin- 1 -yl 1
-246-
(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl]pyrimidine, 1-461
3 -(4-(cis-3 ,5 -dim ethyl -4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin- 1 -
yl)pyrimi din-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-462
3 -(2-((3R, 5 S)-3 -(3 ,5 -dimethy1-4H-1,2,4-triazol-4-y1)-5 -methylpiperidin-
1 -yl)pyrimidin-4-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-463
1 -(ci s-2,6-dimethy1-4-(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazin- 1 -y1)-2-(tetrahydro-2H-pyran-4-yl)ethan- 1 -one, 1-464
3-(2-((3 S,5 S)-3 -(3 , 5 -dimethy1-4H- 1,2,4-triazol-4-y1)-5 -methylpiperidin-
1 -yl)pyrimidin-4-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-465
3-(2-((3 S,5R)-3 -(3 ,5 -dimethy1-4H- 1,2,4-tri azol-4-y1)-5 -methylpi peri
din- 1 -yl)pyrimi din-4-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-466
3 -(2-((3R,5R)-3 -(3 , 5 -dim ethy1-4H- 1,2,4-tri azol-4-y1)-5 -methylpiperi
din- 1 -yl)pyrimi din-4-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-467
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(spiro[2. 2]pentan-1 -yl)methanone, 1-468
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-(2-(1 H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazine- 1 -carb onyl)pyrroli din-2-one, 1-469
3 -(4-(4((2,2-difluorocyclopropyl)methyl)-3 -(1H-pyrazol-4-yl)piperazin- 1 -
yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-470
N-(((2 S,3 S)-3 -methy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin-2-yl)methyl)methanesulfonamide, 1-471
N-((1 -cyclopropy1-4-(2-(6-(difluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-y1)-3 -
methylpiperazin-2-yl)methyl)methanesulfonamide, 1-472
3 -(4-(4-((2-methyl cycl opropyl)methyl)-3 -(1H-pyrazol-4-yl)piperazin- 1 -
yl)pyrimi din-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-473
(S)-64(S)-2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyri din-
3 -yl)pyrimidin-4-
yl)piperazine- 1 -carbonyl)piperidin-2-one, 1-474
3 -(4-(3 -(1H-pyrazol-4-y1)-4-(spiro[2.2]pentan-1-ylmethyl)piperazin-1-
yl)pyrimidin-2-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-475
3 -(4-(4-((2,2-dimethylcyclopropyl)methyl)-3 -(1H-pyrazol-4-yl)piperazin- 1 -
yl)pyrimi din-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-477
N-(5 -(trifluoromethyl)- 1 -(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperidin-3 -yl)methanesulfonamide, 1-478
(R)-(1,3 -dimethyl- 1H-pyrazol-4-y1)(2-methyl-4-(2-(6-(trifluoromethyl)imi
dazo [ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)piperazin- 1 -yl)methanone, 1-479
(S)-(1,3 -dimethyl- 1H-pyrazol-4-y1)(2-methyl-4-(2-(6-(trifluoromethypimi dazo
[ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)piperazin- 1 -yl)methanone, 1-480
3 -(4-((2S,3R)-2-methy1-443 -methyl oxetan-3 -yl)methyl)-3 -(1H-pyrazol-4-
yl)piperazin- 1 -
yl)pyrimidin-2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-481
3 -(4-((2S,3 S)-2-methyl-4-((3 -methyl oxetan-3 -yl)methyl)-3 -(1H-pyrazol-4-
yl)piperazin- 1 -
yl)pyrimidin-2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-482
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(cis-2,6-dimethy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-yl)piperazin-
1-y1)(pyridin-4-yl)methanone, 1-483
(2-( 1H-pyrazol-4-y1)-4-(2-(6-(trifluorom ethypimi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazin- 1 -y1)((lR,2R)-2-fluorocyclopropyl)methanone, 1-485
(cis-2,6-dimethy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-yl)piperazin-
1 -y1)(1 -methyl cycl opropyl)methanone, 1-486
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(tetrahydro-2H-pyran-4-yl)methanone, 1-487
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(1 -(difluoromethyl)cyclopropyl)methanone, 1-488
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)((lR,2R)-2-fluorocyclopropyl)methanone, 1-489
N-(((2R,3 S,6 S)- 1 -cycl opropy1-3 ,6-dimethyl -4-(2-(6-(trifluoromethyl)imi
dazo [ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)piperazin-2-yl)methyl)methanesulfonamide, 1-491
4-(2,2-dimethy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-
4-yl)piperazine-
1 -carb onyl)cycl ohexan- 1 -one, 1-492
N-(((2R,3R,6R)- 1 -cycl opropy1-3 ,6-dimethyl -4-(2-(6-(trifluoromethyl)imi
dazo [ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)piperazin-2-yl)methyl)methanesulfonamide, 1-493
N-(((2 S,3R,6R)- 1 -cycl opropy1-3 ,6-dimethy1-4-(2-(6-(trifluoromethyl)imi
dazo [ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)piperazin-2-yl)methyl)methanesulfonamide, 1-494
N-((4-(2-(6-(difluoromethyl)imidazo[ 1,2-a] pyridin-3 -yl)pyrimidin-4-y1)-3 -
(trifluoromethyl)piperazin-2-yl)methyl)methanesulfonami de, 1-496
(2R,6R)-4-(2-(6-(difluoromethyl)imi dazo [ 1,2-a]pyri din-3 -yl)pyrimidin-4-
y1)-2-methyl-6-(3 -
methyl- 1,2,4-oxadi azol-5 -yl)morpholine, 1-497
(2 S,6 S)-4-(2-(6-(difluoromethyl)imidazo[ 1,2-a] pyridin-3 -yl)pyrimidin-4-
y1)-2-methy1-6-(3 -
methyl- 1,2,4-oxadi azol-5 -yl)morpholine, 1-498
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(((3 S,5R)-1-(4-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-2-y1)-
5 -
methylpi peri din-3 -yl)imino)dimethyl-M-sulfanone, 1-499
N-((S)- 1-((2S,3 S)- 1 -cycl opropy1-3 -methyl -4-(2-(6-(trifluoromethyl)imi
dazo [ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)piperazin-2-yl)ethyl)methanesulfonamide, 1-500
1 -(ci s-2,6-dimethy1-4-(2-(6-(trifluoromethyl)imi dazo [ 1,2-a]pyri din-3 -
yl)pyrimi din-4-
yl)piperazin- 1 -y1)-2-(oxetan-3 -yl)ethan- 1 -one, 1-501
(S)-3 -(443 -(1H-pyrazol-4-y1)-4-(2-oxaspiro[3 .3 ]heptan-6-yl)piperazin-1 -
yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-502
(R)-3 -(4-(4-cyclopropy1-3 -(1H-pyrazol-4-yl)piperazin- 1 -yl)pyrimi din-2-y1)-
6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-503
(R)-3 -(443 -(1H-pyrazol-4-y1)-4-(2-oxaspiro [3 .3 ]heptan-6-yl)piperazin- 1 -
yl)pyrimi din-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-504
N-((R)- 1-((2R, 3R)- 1 -cyclopropy1-3 -methy1-4-(2-(6-(trifluoromethyl)imi
dazo [ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)piperazin-2-yl)ethyl)methanesulfonamide, 1-505
N-((R)- 1-((2 S,3 S)- 1 -cyclopropy1-3 -methy1-4-(2-(6-
(trifluoromethyl)imidazo[ 1,2-a] pyri din-3 -
yl)pyrimidin-4-yl)piperazin-2-yl)ethyl)methanesulfonamide, 1-506
N-((S)- 1 -((2R,3R)- 1 -cycl opropy1-3 -methyl -4-(2-(6-(trifluoromethyl)imi
dazo [ 1,2-a]pyri din-3 -
yl)pyrimidin-4-yl)piperazin-2-yl)ethyl)methanesulfonamide, 1-507
3- {2-[(R)-4-Cyclopropy1-3 -(1H-pyrazol-4-y1)-pip erazin- 1 -y1]-pyrimi din-4-
y! } -6-trifluoromethyl-
imidazo[1,2-a]pyridine, 1-508,
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1-y!)(3 -hydroxy-3 -methyl cycl obutyl)methanone, 1-509
3 -(4-(4-((1 -m ethyl cycl opropyl)methyl)-3 -(1H-pyrazol-4-yl)piperazin- 1 -
yl)pyrimi din-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-510
4- [(2R, 3 S)-4- { [ 1 -(methoxymethyl)cyclobutyl]methyl } -2-methy1-3 -(1H-
pyrazol-4-yl)piperazin-
1 -y1]-246-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl]pyrimidine, 1-511
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4- [(2 S,3 S)-4- { [ 1 -(methoxymethyl)cyclobutyl]methyl 1-2-methyl-3 -(1H-
pyrazol-4-yl)piperazin- 1 -
y1]-246-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl]pyrimidineõ 1-512
(6,7-dihydro-4H-pyrazol o [5, 1-c] [ 1,4] oxazin-2-y1)(ci s-2,6-dim ethy1-4-(2-
(6-
(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-yl)piperazin-1-
yl)methanone, I-
513
1 -(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)-2-hydroxy-2-methylpropan- 1 -one, 1-514
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1-y1)(5 -methyli soxazol-4-yl)methanone, 1-515
N-(((2R,3 S)- 1 -cyclopropy1-4-(2-(6-(difluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-y1)-
3 -methylpiperazin-2-yl)methyl)methanesul fonami de, 1-516
N-(((2 S,3R)- 1 -cyclopropy1-4-(2-(6-(difluoromethyl)imidazo[ 1,2-a]pyridin-3 -
yl)pyrimidin-4-y1)-
3 -methylpiperazin-2-yl)methyl)methanesul fonami de, 1-517
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1-y1)(4-methyl- 1,2,5 -oxadi azol-3 -yl)methanone, 1-518
(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1-y1)(3 , 5 -dimethyli soxazol-4-yl)methanone, 1-519
3 -(4-((R)-4-(((R)-6-oxaspiro [2. 5 ] octan- 1 -yl)methyl)-3 -(1H-pyrazol-4-
yl)piperazin- 1 -
yl)pyrimidin-2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-520
3 -(4-((S)-4-(((S)-6-oxaspiro[2. 5] octan-1 -yl)methyl)-3 -(1H-pyrazol-4-
yl)piperazin- 1 -
yl)pyrimidin-2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-521
3 -(4-((S)-4-(((R)-6-oxaspiro[2. 5] octan- 1 -yl)methyl)-3 -(1H-pyrazol-4-
yl)piperazin-1 -
yl)pyrimidin-2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-522
3 -(4-((R)-4-(((S)-6-oxaspiro[2. 5] octan- 1 -yl)methyl)-3 -(1H-pyrazol-4-
yl)piperazin-1 -
yl)pyrimidin-2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-523
((2S,6S)-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)-6-
methylmorpholin-2-yl)m ethanol, 1-524
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N-(1 -(4-(6-(difluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-2-y1)-5-
(trifluoromethyl)piperidin-3 -yl)methanesulfonamide, 1-525
3 -(4-((R)-4-(((R)-2,2-dimethylcyclopropyl)methyl)-3 -(1H-pyrazol-4-
yl)piperazin- 1 -
yl)pyrimidin-2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-526
3 -(4-((S)-4-(((S)-2,2-dimethylcyclopropyl)methyl)-3 -(1H-pyrazol-4-
yl)piperazin-1-yl)pyrimidin-
2-y1)-6-(trifluoromethypimidazo[1,2-a]pyridineõ 1-527
3 -(4-((S)-4-(((R)-2,2-dimethylcyclopropyl)methyl)-3 -(1H-pyrazol-4-
yl)piperazin- 1 -
yl)pyrimidin-2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-528
3 -(4-((R)-4-(((S)-2,2-dimethylcyclopropyl)methyl)-3 -(1H-pyrazol-4-
yl)piperazin- 1 -
yl)pyrimidin-2-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-529
N-((4-(2-(6-(difluoromethyl)imidazo[ 1,2-a] pyridin-3 -yl)pyrimidin-4-y1)-3 -
methyl- 1 -(oxetan-3 -
yl)piperazin-2-yl)methyl)methanesulfonamide, 1-530
N-(1 -(2-(6-(difluoromethyl)imidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-y1)-5-
(trifluoromethyl)piperidin-3 -yl)methanesulfonamide, 1-531
(R)-3 -(443 -(1H-pyrazol-4-yl)piperazin- 1 -yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-
a]pyridine, 1-532
(S)-3 -(443 -(1H-pyrazol-4-yl)piperazin-1 -yl)pyrimidin-2-y1)-6-
(trifluoromethyl)imidazo[ 1,2-
a]pyridine, 1-533
3 -(4-((2S,3R)-2-methy1-3 -(1H-pyrazol-4-yl)piperazin- 1 -yl)pyrimi din-2-y1)-
6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-534
3 -(4-((2S,3 S)-2-methyl -3 -(1H-pyrazol-4-yl)piperazin- 1 -yl)pyrimi din-2-
y1)-6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-535
3 -(4-((2R, 3R)-2-methyl-3 -(1H-pyrazol-4-yl)piperazin- 1 -yl)pyrimi din-2-y1)-
6-
(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-536
4-[(2R, 3 S)-2-methyl-3 -(1H-pyrazol-4-yl)piperazin-1 -y1]-2-[6-
(trifluoromethyl)imidazo[ 1,2-
a]pyridin-3 -yl]pyrimidine, 1-537
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(2R,6R)-4-(2-(6-chl oro-7-fluoroimi dazo [ 1,2-a]pyri din-3 -yl)pyrimi din-4-
y1)-2-methy1-6-(5 -
methyl- 1H-pyrazol-4-yl)morpholine, 1-538
(2 S,6 S)-4-(2-(6-chloro-7-fluoroimidazo[ 1,2-a]pyridin-3 -yl)pyrimidin-4-y1)-
2-methyl -6-(5 -
methyl- 1H-pyrazol-4-yl)morpholine, 1-539
(2R,6 S)-4-(2-(6-chl oro-7-fluoroimi dazo [ 1,2-a]pyri din-3 -yl)pyrimi din-4-
y1)-2-methyl -645 -
methyl- 1H-pyrazol-4-yl)morpholine, 1-540
N-(((2R, 3 S)- 1 -cycl opropyl -3 -methyl-4-(4-(6-(trifluoromethyl)imi dazo [
1,2-a]pyri din-3 -
yl)pyrimidin-2-yl)piperazin-2-yl)methyl)methanesulfonamide, 1-541
3 -(2-((S)-3 -(1H-pyrazol-4-y1)-4-(((R)-tetrahydro-2H-pyran-3 -
yl)methyl)piperazin- 1 -
yl)pyrimidin-4-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-542
N-{ (2 S,3R)- 1 -Cyclopropy1-3 -methyl-444-(6-trifluoromethyl-imidazo[1,2-
a]pyridin-3 -y1)-
pyrimidin-2-y1]-piperazin-2-ylmethyl} -methanesulfonamide, 1-543
3 -(2-((R)-3 -(1H-pyrazol-4-y1)-4-(((S)-tetrahydro-2H-pyran-3 -
yl)methyl)piperazin- 1 -
yl)pyrimidin-4-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-544
3 -(2-((R)-3 -(1H-pyrazol-4-y1)-4-(((R)-tetrahydro-2H-pyran-3 -
yl)methyl)piperazin- 1 -
yl)pyrimidin-4-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-545
3 -(2-((S)-3 -(1H-pyrazol-4-y1)-4-(((S)-tetrahydro-2H-pyran-3 -
yl)methyl)piperazin- 1 -
yl)pyrimidin-4-y1)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, 1-546
(2R,3R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)- 1 -
cyclopropy1-3 -
methylpiperazine-2-carboxamide, 1-547
(2S,3 S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)- 1 -
cyclopropy1-3 -
methylpiperazine-2-carboxamide, 1-548
(S)-(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(5 -methyli soxazol-4-yl)methanone, 1-549
(R)-(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3 -
yl)pyrimidin-4-
yl)piperazin- 1 -y1)(5 -methyli soxazol-4-yl)methanoneõ 1-550
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1-(2-(1H-pyrazol-4-y1)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
yl)pyrimidin-2-
yl)piperazine-1-carbonyl)cyclopropane-1-carbonitrile, 1-551
3-(4-((R)-3-(1H-pyrazol-4-y1)-4-(((R)-spiro[2.2]pentan-1-y1)methyl)piperazin-1-
y1)pyrimidin-2-
y1)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, 1-552
3-(4-((S)-3-(1H-pyrazol-4-y1)-4-(((S)-spiro[2.2]pentan-1-yl)methyl)piperazin-1-
y1)pyrimidin-2-
y1)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, 1-553
3-(4-((S)-3-(1H-pyrazol-4-y1)-4-(((R)-spiro[2.2]pentan-1-yl)methyl)piperazin-1-
y1)pyrimidin-2-
y1)-6-(trifluoromethyl)imidazo[1,2-a]pyridineõ 1-554
3-(4-((R)-3-(1H-pyrazol-4-y1)-4-(((S)-spiro[2.2]pentan-1-yl)methyl)piperazin-1-
yl)pyrimidin-2-
y1)-6-(trifluoromethyl)imidazo[1,2-a]pyridineõ 1-555
(S)-6-(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
yl)pyrimidin-4-
yl)piperazin-1-y1)-2-thiaspiro[3.3]heptane 2,2-dioxide, 1-556
(R)-6-(2-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethypimidazo[1,2-a]pyridin-3-
yl)pyrimidin-4-
yl)piperazin-1-y1)-2-thiaspiro[3.3]heptane 2,2-dioxide, 1-557
(S)-1-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-
yl)piperidine-3-carboxamide,
1-558
6-chloro-3-(4-((3R,5S)-3-methy1-5-(1H-pyrazol-4-y1)piperidin-1-y1)pyrimidin-2-
y1)imidazo[1,2-
a]pyridine, 1-559
(2S,6R)-2-methy1-6-(1H-pyrazol-4-y1)-4-(2-(6-(trifluoromethyl)imidazo[1,2-
a]pyridin-3-
yl)pyrimidin-4-yl)morpholine, 1-560
(2R,6S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-y1)-2-methy1-6-(5-
methy1-1H-
pyrazol-4-yl)morpholine, 1-561
(2S,6S)-6-methy1-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-
4-
yl)morpholine-2-carboxamide, 1-562
6-chloro-3-(4-((2S,3R,5S)-2,5-dimethy1-3-(1H-pyrazol-4-y1)piperazin-1-
y1)pyrimidin-2-
y1)imidazo[1,2-a]pyridine, 1-563
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(2R,6 S)-2-m ethyl -6-(1H-pyraz ol-4-y1)-4-(2-(6-(tri fluorom ethyl)imi dazo
[1,2-a] pyri di n-3 -
yl)pyrimidin-4-yl)morpholine, 1-564
3-(4-((2R,3 S)-2-m ethy1-4-(ox etan-3 -y1)-3 -(1H-pyrazol -4-yl)pip erazin-l-
yl)pyrimi din-2-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-565
(2R,6 S)-4-(2-(6-chl oroimi dazo [1,2-a] pyri din-3 -yl)pyrimi din-4-y1)-2-
methy1-6-(1H-pyrazol-4-
yl)morpholine, 1-566
3-(4-((3R,5 S)-3 -methy1-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-y1)-6-
(trifluoromethypimidazo[1,2-a]pyridine, 1-567
(2 S,6R)-4-(2-(6-chl oro-7-fluoroimi dazo [1,2-a] pyri din-3 -yl)pyrimi din-4-
y1)-2-m ethyl -6-(1H-
pyrazol-4-yl)morpholine, 1-568
(((3R,5R)-1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-4-y1)-
5-
m ethylpi p eri din-3 -yl)imino)dimethyl-M-sulfanone, 1-569
Example 26: Human IL-2 assay for GCN2 inhibition
[00488] Tumor microenvironment is profoundly immuno-suppressive. This may be
attributed
to the depletion of amino acids (like arginine and tryptophan) which triggers
the activation of
GCN2 in immune cells, including T cell and myeloid cells. In T cells,
activation of GCN2 leads
to reduce effector functions of CD8 T cells and induction and/or maintenance
of immuno-
suppressive T-regs. Inhibition of that immuno-suppressive response by GCN2
inhibitors enables
an anti-cancer immune response by activating effector T-cells. Herein we
describe an in-vitro
system we established using human T-cells stimulated in low amino acid
condition in order to
engage the GCN2 biology. The method described involves the modulation of IL-2
levels secreted
by human T cells in responses to the GCN2 inhibitors disclosed herein.
[00489] Amino acid-free RPMI was reconstituted with all but one of the amino
acids found in
standard RMPI (e.g. Arginine, Tryptophan), 10% charcoal-stripped fetal bovine
serum, 100
Units/mL penicillin and 0.1mg/mL streptomycin. Primary human pan T-cells were
isolated using
Pan T Cell Isolation Kit, human (MACS Miltenyi biotech Cat# Order no. 130-096-
535) from
apheresis cones and 5x104 pan T-cells per well. The purified T cells are
seeded in NuncTM 96
Well Polystyrene Round Bottom Microwell Plates (the cells are rested in No TRP
media in a 15m1
falcon tube in the incubator for 30-45 minutes while titrations for tryptophan
and the GCN2
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inhibitor compound are made) A plate matrix was developed to titrate both a
GCN2 inhibitor and
the amino acid of interest ranging from "No Amino Acid" condition, up to the
concentration found
in the regular RPMI media (20 M for TRP and 950 M for Arginine). The cells
were incubated
for 30 min at 37 C with the GCN2 inhibitor and then stimulated with 5x104 anti-
CD3/CD28
dynabeads per well. After 96 hours of incubation the IL-2 level in the
supernatant were measured
using ELISA (R&D systems Cat# DY202 (Human IL-2 DuoSet ELISA). Data were
plotted in
GraphPad Prism software and EC50 is calculated.
Table 6. EC50 values based on IL-2 secretion from T cells
[00490] +++ for EC50 <100 nM; ++ for ECso in the 100-500 nM range; + for
EC50 >500 nM;
and "-" for not active
IL2/T-cell ECso
Compound I#
(nM)
1-102 ++
1-116 +++
1-123 +, -
1-124 ++,+++
1-125 +++, ++, +
1-126 ++
1-127 +++
1-128
1-134
1-135 ++
1-136 +++, ++
1-137 ++
1-148 ++
1-154
1-160 ++
1-170 ++
1-176 +++
1-179 ++
1-185
1-191
1-200 ++
1-209 ++
1-223 ++
1-247 +++
1-248 ++
1-249 ++
1-250
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1-259 +++
1-293 +++
1-314 -
1-315 ++
1-323 +
1-354 ++
1-359 ++
1-366 +++
1-409 +
1-473 ++
1-481 +++
1-482 +
1-495 +
1-499 +
1-504 ++
1-547 ++
1-558 ++
1-559 +++
1-560 +++
1-561 ++
1-562 ++
1-563
1-564 +++
1-565 +++
1-566 +++
1-567 +++
1-568 ++
1-569 ++
1-562 ++
[00491] While we have described a number of embodiments of this invention, it
is apparent that
our basic examples may be altered to provide other embodiments that utilize
the compounds and
methods of this invention. Therefore, it will be appreciated that the scope of
this invention is to
be defined by the appended claims rather than by the specific embodiments that
have been
represented by way of example.
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